Introduction And Aim of the work

Transcription

1 Review of Literature Introduction And Aim of the work Obstructive sleep apnea is a sleep disorder due to repetitive obstructions of the collapsible pharyngeal airway. It is therefore natural to search for local anatomical abnormalities to unveil the possible causes of the disease, and to look for potential curative interventions. Obstructive sleep apnea syndrome (OSAS) is a highly prevalent disease leading to severe medical consequences if left untreated (Basto and Rodenstein, 2006). OSAS has been recognised as an independent risk factor for disorders such as hypertension, cardiovascular disease and sleepinessrelated accidents. Currently, it is considered to be a systemic disease (Pataka A and Riha, 2009). In the past, the upper airway was evaluated by differential pressure measurements, allowing calculation of upper airway resistance and electromyographic (EMG) activiy of various upper airway muscles (Horner, 1996). Those modalities, however, do not provide anatomical representation of the soft tissue structures surrounding the airway. Moreover, mechanical action can not be inferred from these modalities, although providing a wealth of information on upper airway physiology, are unable to evaluate the soft tissue structures. knowledge of the morphology and mechanical behavior of the soft tissue structures is essential for a more complete understanding of the physiology of the upper airway, Such information has been with imaging technology (Horner, 1996).

2 Review of Literature Studies with nasal pharyngoscopy, fluoroscopy, conventional and electron beam computed tomography have been used to examine the anatomy of the pharynx (size of the upper air way structures) in patients with this disorder (Malhotra et al., 2002). However, these studies have disadvantages of invasive and /or ionizing radiation. patients with OSA are imaged to identify potential sites of upper airway obstruction prior to surgical intervention (Schwab, 2009). Obesity is a key risk factor for OSAS, in a population-based prospective study of 690 randomly selected Wisconsin residents, a 10% weight gain was associated with a 6-fold increase in the odds of development of sleep apnea (Suratt et al., 1992). The behavior of the relaxed pharynx is partly dependent on the transmural pressure. An increase in transmural pressure promotes pharyngeal patency, whereas a decrease in the pressure promotes pharyngeal collapse. The transmural pressure at which the pharyngeal area decreases to zero is called the closing pressure. The pharynx becomes increasingly susceptible to collapse as its luminal area decreases (Qureshi et al., 2003). CPAP requirements also may change over longer periods. Weight loss may reduce the level of required CPAP pressure, while weight gain often necessitates the use of higher pressures (Victor, 2004). So in our studies we will use other imaging technique to objectively quantify the measurement of the upper air way structures to fully understand the anatomical risk factors for obstructive sleep apnea with avoidance of these disadvantages.

3 Review of Literature So our aim -with taken in consideration the above mentioned literature- is to study the anatomico-physiological risk factors of obstructive sleep apnea syndrome and its relation to the outcome of different treatment modalities.

4 Review of Literature Obstructive Sleep Apnea Syndrome Obstructive sleep apnea is the most common cause of sleep related breathing disorder and characterized by repeated episodes of complete or partial upper airway obstruction during sleep causes loud snoring, oxyhemoglobin desaturations and frequent arousals being responsible for a reduced depth of sleep. As a result, affected persons have unrestful sleep and excessive daytime sleepiness. The disorder is associated with hypertension, impotence and emotional problems. Because obstructive sleep apnea often occurs in obese persons with comorbid conditions, its individual contribution to health problems is difficult to discern (Punjabi & Polotsky, 2007). Sleep-disordered breathing refers to an abnormal respiratory pattern (ie, apneas, hypopneas, or respiratory effort related arousals) or an abnormal reduction in gas exchange (ie, hypoventilation) during sleep. It alters sleep duration and architecture, which may result in daytime symptoms, signs, and/or organ system dysfunction (Iber et al., 2007). Sleep related breathing disorders are characterized by abnormal respiration during sleep; they occur in both adults and children. There are three major sleep related breathing disorders divided according to their etiology: The obstructive sleep apnea syndromes include adult obstructive sleep apnea-hypopnea and pediatric obstructive sleep apneahypopnea.

5 Review of Literature The central sleep apnea syndromes include primary central sleep apnea, central sleep apnea due to Cheyne-Stokes breathing, central sleep apnea due to high altitude periodic breathing, central sleep apnea due to a medical condition, central sleep apnea due to drug, medication, or substance use, and primary sleep apnea of infancy. The sleep related hypoventilation/hypoxemia syndromes include idiopathic sleep related nonobstructive alveolar hypoventilation, congenital central alveolar hypoventilation syndrome, and sleep related hypoventilation/hypoxemia due to a medical condition (AASM, 2005). The 2nd edition of the International Classification of Sleep Disorders (ICSD-2) was published by the American Academy of Sleep Medicine in This system classifies sleep disorders into eight major categories: Insomnia Sleep related breathing disorders Hypersomnias of central origin Circadian rhythm sleep disorders Parasomnias Sleep related movement disorders Isolated symptoms and normal variants Other sleep disorders AASM Manual, 2007 define the followings: Apnea: Apnea is the cessation, or near cessation, of airflow for 10 seconds. It exists when airflow is less than 20 percent of baseline for at least ten seconds in adults. In children, the duration criteria are shorter.

6 Review of Literature Hypopnea: Hypopnea is a reduction of airflow to a degree that is insufficient to meet the criteria for an apnea and the American Academy of Sleep Medicine, recommends that hypopnea be scored when all of the following four criteria are met Airflow decreases at least 30 percent from baseline There is diminished airflow lasting at least ten seconds At least 90 percent of the duration of diminished airflow is spent with airflow that is at least 30 percent less than baseline Decreased airflow is accompanied by at least four percent oxyhemoglobin desaturation Alternative scoring criteria have also been endorsed by AASM Manual, 2007: Airflow decreases at least 50 percent from baseline There is diminished airflow lasting at least ten seconds At least 90 percent of the duration of diminished airflow is spent with airflow that is at least 30 percent less than baseline Decreased airflow is accompanied by at least three percent oxyhemoglobin desaturation and an arousal Respiratory effort related arousals: Respiratory effort related arousals (RERAs) exist when there is a sequence of breaths that lasts at least ten seconds, is characterized by increasing respiratory effort or flattening of the nasal pressure waveform, and leads to an arousal from sleep, but does not meet the criteria of an apnea or hypopnea. The inspiratory airflow or tidal volume is maintained during these episodes, but requires increased respiratory effort. RERAs (>5 to 15 events per hour) associated with daytime sleepiness was previously called "upper airway resistance syndrome," a subtype of obstructive sleep apnea-hypopnea (OSAH).

7 Review of Literature Obstructive apnea: An obstructive apnea occurs when airflow is absent or nearly absent, but ventilatory effort persists. It is caused by complete, or near complete, upper airway obstruction Central apnea: A central apnea occurs when both airflow and ventilatory effort are absent Mixed apnea: During a mixed apnea, there is an interval during which there is no respiratory effort (ie, central apnea pattern) and an interval during which there are obstructed respiratory efforts (The central apnea pattern usually precedes the obstructive apnea pattern. Apnea-hypopnea index: The apnea hypopnea index (AHI) is the total number of apneas and hypopneas per hour of sleep. The AHI is most commonly calculated per hour of total sleep Respiratory disturbance index (RDI): The respiratory disturbance index (RDI) is the total number of events (eg, apneas, hypopneas, and RERAs) per hour of sleep. The RDI is generally larger than the AHI, because the RDI considers the frequency of RERA, while the AHI does not (Iber et al., 2007) The evaluation of OSA severity is obtained through the assessment of the apnea-hypopnea index (AHI). The American Academy of Sleep Medicine Task Force recommends an AHI 5 associated with the presence of symptoms such as excessive daytime sleepiness as a criterion for OSAS diagnosis. Subjects who have an AHI < 5 but who snore most of the night on most nights are classified as habitual snorers (American Academy of Sleep Medicine Task Force, 1999).

8 Review of Literature Other indices of OSAS severity include oxygen desaturation index (ODI, i.e., the average number of significant oxygen desaturations per hour of sleep), and the arousal index (number of EEG arousals per hour of sleep). More recently proposed methods for quantification of OSAS are the cross-power index (CPI, the integral of the cross-spectrum modulus between concomitant fluctuations in systolic blood pressure and blood oxygen saturation), aimed at assessing the cardiovascular impact of OSAS, and the peripheral arterial tonometry index (PAT), an indicator of acute arousal responses to OSA. cross-power index (CPI) provide a quantitative assessment of the beat-by-beat changes in systolic blood pressure which measured noninvasively with a finger-pressure device (Portapres; Finapres Medical Systems, Arnheim, The Netherlands) that follow changes in blood oxygen saturation continuously assessed by pulse oxymetry. The relation between these changes is quantified as the modulus of the transfer function between fluctuations in blood oxygen saturation and the corresponding fluctuations in systolic blood pressure (Castiglioni et al., 2002).

9 Review of Literature Prevalence Of OSAHS It is estimated that ~20% of a general population displays obstructive apneas (AHI 5), whereas a full clinical picture of OSAS is seen in 1 5% of men and in 0.5 2% of women of premenopausal age The prevalence of habitual snoring is even higher, reaching 25 35%. SDB, including snoring and OSAS display a peak of prevalence in middle-aged subjects, with a decline after the age of 65 Indeed, the increase in the overall prevalence of sleep apneas with age seems to depend mainly on an increased prevalence of CSA. In postmenopausal women, the OSAS prevalence tends to increase, particularly in wom,en without hormone replacement therapy, but it remains lower than in men in the same age stratum (Young et al., 2003). The main epidemiological factor associated with the presence of OSAS is an increased body mass. The increasing prevalence of OSAS in Western countries parallels the progressive increase in frequency of overweight and obesity, OSAS being seen in as much as 40% of obese men and 70% of OSAS patients being obese (Gozal and O'Brien, 2004).

10 Review of Literature Risk factors of obstructive sleep apnea Ι- Upper airway Anatomical Risk Factors: The human upper airway is a unique multipurpose structure involved in performing functional tasks such as speech, swallowing of food/liquids, and the passage of air for breathing. The anatomy and neural control of the upper airway have evolved to enable these various functions. The airway, therefore, is composed of numerous muscles and soft tissue but lacks rigid or bony support. Most notably, it contains a collapsible portion that extends from the hard palate to the larynx. Although the ability of the upper airway to change shape and momentarily close is essential for speech and swallowing during wakefulness, this feature also provides the opportunity for collapse at inopportune times such as during sleep (Burger et al., 1992). From a purely anatomic perspective, a narrow upper airway is generally more prone to collapse than a larger one. Accordingly, on the whole, the cross-sectional area of the upper airway as measured by computed tomography and magnetic resonance imaging during wakefulness is reduced in patients with OSA compared with subjects without OSA). Further, the arrangement of the surrounding soft tissues appears to be altered in patients with OSA, which may place the upper airway at risk for collapse (Schwab et al., 1995). Imaging studies during wakefulness, however, are complicated to interpret because ongoing upper airway dilator muscle activity may lead to potential differences between groups, due to factors other than anatomy. In addition to these imaging measures, a methodology to determine the pressure at which the upper airway collapses during sleep (Pcrit) as a gauge of passive upper airway anatomy is also in concordance with reduced upper airway caliber in patients with OSA. Perhaps the most definitive data come from Isono

11 Review of Literature and colleagues, who observed increased closing pressure (more collapsible) in OSA as compared with control subjects under conditions of general anesthesia and muscle paralysis (Isono et al., 1997). Thus, in aggregate, multiple methodologies have shown that patients with OSA have anatomic compromise making these individuals susceptible to pharyngeal collapse during sleep (Schwartz et al., 1998 and Patil et al., 2007). The pharyngeal airway is enclosed along its length by bones, including the nasal turbinates, hard palate of the maxilla, mandible, hyoid, and cervical vertebrae, and by soft tissues, including the tongue, soft palate, tonsillar pillars, pharyngeal mucosa and muscles, epiglottis, pharyngeal fat pads, and blood vessels of the neck. In general, the ratio of upper airway soft tissue mass is disproportionately high for the space made available by the bony structures enveloping the pharynx in OSA patients. Thus an excess of soft tissue and/or a small bony cage impinges on the pharyngeal lumen in most OSA patients (Katsantonis, 1994). Obstructive apneas and hypopneas occur because of intermittent complete and partial collapse of the pharynx, respectively, during sleep. The pharynx can be divided into four segments: 1) the nasopharynx, which extends from the nasal turbinates to the superior part of the soft palate, 2) the retropalatal pharynx, from the hard palate to the caudal margin of the soft palate, 3) the retroglossal segment, from the caudal margin of the soft palate to the tip of the epiglottis, and 4) the hypopharynx, from the epiglottis to the larynx. The retropalatal and retroglossal pharynx are often referred to together as the oropharyngeal segment and the junction of the retropalatal and retroglossal pharynx as the velum (Schwab et al., 1995) (see figure 1).

12 Review of Literature Figure (1): Normal airway. The soft palate and uvula are normal in length and total size. The tongue is normal in size and is angled forward. The upper airway at the level of the nasopharynx, oropharynx and hypopharynx is normal in size and contour (Olsen and Kern 1990). The sites of collapse during sleep have been assessed with a variety of techniques, including pharyngeal pressure catheters placed at various sites in the UA, cine fluoroscopy, video endoscopy, computerized tomography, and MRI. Pharyngeal collapse can occur at end expiration or at the beginning of inspiration (Morrell, 1998). The collapse starts initially in the retropalatal/oropharyngeal areas in most (75%) OSA patients. This is followed by caudal extension of the collapse to the base of the tongue in 44% of patients and, finally, to the hypopharyngeal region in 33% of patients. In a minority of patients, the initial site of collapse is the hypopharynx (Bhattacharyya, 2000). The extent of the collapsed segment varies between sleep stages, with a more caudal extension often occurring during rapid eye movement (REM) sleep (Shepard and Thawley, 1990). In OSA patients with more severe disease, the primary site of collapse is reproducible from night to

13 Review of Literature night in 80% of patients. Airway reopening at the termination of apnea usually occurs during inspiration, its onset is sudden in half of cases and gradual in the other half, and it extends from the caudal to the cranial portion of the occluded segment (Pepin, 1992&Rollheim, 2001). Compared with normal subjects, habitual snorers with or without OSA have a generalized narrowing of the pharyngeal lumen, whether or not they are obese (Suratt, 1983 & Bradley, 1986). The pharyngeal lumen of normal subjects is generally elliptical in shape, with the long axis in the lateral dimension. In contrast, the lumen of snorers and OSA patients during wakefulness and sleep is circular or elliptical, with the long axis in the anterior-posterior dimension as a result of medial displacement of the lateral pharyngeal walls. These differences in shape are most pronounced at the retropalatal level and are most notable when subjects are asleep. Accordingly, structures adjacent to the lateral pharynx displace the lumen medially, indicating that these structures play an important role in narrowing the pharyngeal lumen (Schwab, 1995). Abnormalities of the bony cage enveloping the oropharyngeal cavity are frequently observed in OSA patients. The most common abnormalities are hypoplasia and/or retrodisplacement of the maxilla and mandible, restricting space in the oropharyngeal cavity As a consequence, the tongue, soft palate, and soft tissues surrounding the upper airway are displaced posteriorly, impinging on the lumen. Extreme examples of such abnormalities occur in subjects with congenital craniofacial dysplasia, such as those with Aperts, Pierre-Robin, and Treacher-Collins syndromes. These syndromes cause maxillary and/or mandibular hypoplasia and are associated with very high prevalence of OSA (Mixter, 1990 & Watanabe, 2002).

14 Review of Literature Cephalometric studies have shown retropositioning and shortening of the mandible and maxilla, even in the absence of distinct craniofacial abnormalities, in OSA patients compared with normal subjects. Shorter and more posteriorly displaced mandibles have been confirmed in up to two-thirds of OSA patients and correlate with decreased pharyngeal size (figure2-4). Medial displacement of the mandibular rami may also occur and reduce intramandibular volume (Shelton 1993&Johal and Conaghan, 2004)). Figure (2): Normal airway: no obstruction in the upper airway is noted (Madani,2007).

15 Review of Literature Figure (3): Hypopnea; partial obstruction of the upper airway. There is a partial narrowing of the pharyngeal airway. The vibration of tissues in the airway to include uvula, soft palate, obstructive tonsils, deviated septum, hypertrophied nasal turbinate and mandibular or bimaxillary retrognathism are amongst various factors causing snoring and obstructed sleep apnea (Madani,2007). Figure (4): Obstructive sleep apnea; the flow of air is blocked through the upper airways and patient is deprived of receiving vital oxygen deemed necessary for normal body function (Madani,2007)..

16 Review of Literature In contrast to most other mammals, the hyoid bone of humans is not attached to the cervical spine. This detachment of the hyoid appears to be related to the development of speech but makes the upper airway much more compliant and susceptible to collapse in humans than in other mammals because of the lack of rigid bony support(davidson, 2003). Compared with normal subjects, the hyoid bone is displaced inferiorly in OSA patients. This inferior displacement of the hyoid bone is accompanied by an inferior displacement of the tongue into the hypopharyngeal area: the more inferiorly displaced the hyoid, the greater the apnea-hypopnea index (Kato, 2000). Whether caudal displacement of the hyoid bone in OSA patients is the result of the inferior shift of the tongue is not clear (Watanabe, 2002). All these anatomic variations reduce the size of the upper airway in OSA patients. However, the reduction in mandibular length appears to be the most common and, probably, most important skeletal., abnormality predisposing to OSA. This point is emphasized by the observation that mandibular advancement by appliances or surgery increases the size of the pharyngeal lumen and reduces the severity of OSA (Young and McDonald, 2004; Riha, 2005 & Rachmiel, 2005). Soft tissues form the walls of the pharynx and include the tongue, uvula, tonsillar pillars, soft palate, blood vessels, lymphoid tissue, pharyngeal fat pads, upper airway muscles, pharyngeal mucosa, and lateral pharyngeal walls. Enlargement of the soft tissues through hypertrophy, inflammation, or edema may reduce the diameter of the upper airway. MRI studies have demonstrated increased soft tissue mass surrounding the upper airway and, hence, reduced upper airway size in the retropalatal and, to a lesser extent, the retroglossal area of OSA

17 Review of Literature patients compared with control subjects (Bradley etal.,1986)(fig.5). The larger the volumes of the lateral pharyngeal walls, tongue, and total soft tissue, the greater are the odds of OSA (Schellenberg, 2000; Schwab, 2003). Figure (5): Comparison of a midsagittal MR image of a normal subject and patient with sleep apnea. Airway caliber is smaller in the apneic. Soft palate and tongue area are larger in the apneic (Bradley etal.,1986). Although the lateral pharyngeal fat pads in OSA patients are enlarged compared with those in control subjects (Shelton, 1993), these fat pads do not necessarily impinge on the UA lumen (Schwab, 1995). Upper airway edema, especially in the lateral pharyngeal walls, has been demonstrated on tissue specimens and with MRI scanning and can contribute to soft tissue enlargement in OSA patients (Leiter, 1996; Shepard, 1996 & Anastassov and Trieger, 1998). Nuchal or pharyngeal mucosal edema could result from distension of and/or increased pressure in the neck veins, edema formation from vascular congestion or inflammation secondary to the trauma caused by vibration of tissues during snoring, or pulmonary hypertension from recurrent hypoxic pulmonary artery vasoconstriction. The jugular veins are located adjacent to the lateral walls of the pharynx, and because these walls appear to be the most compliant part of the pharynx, they would be most susceptible to

18 Review of Literature medial displacement in the face of jugular venous distension in fluidoverload states, such as biventricular heart failure, cor-pulmonale, and renal failure). The soft palate and tongue are also enlarged in OSA patients (Bradley, 1985). In adults and, particularly, children, adenotonsillar hypertrophy may increase the risk of OSA (Greenfeld, 2003). The length of the pharynx may also be a significant predisposing factor for OSA. Cephalometric studies demonstrate a lengthening of the pharynx in men with OSA compared with those without OSA (Pae, 1997), which may predispose to upper airway collapse by increasing the length of the collapsible portion of the lumen (Malhotra, 2002). A reduction in the distance from the soft palate to the posterior oropharyngeal wall, which is partly a result of retrodisplacement of the maxilla, has also been observed in OSA patients. A thickening of the soft palate and enlargement of the uvula have been noted in OSA patients (Ingman, 2004). The upper airway begins in the nares, and nasal obstruction may play a role in upper airway collapsibility; however, this remains a point of conjecture. Nasal obstruction can be caused by a deviated nasal septum or mucosal swelling from allergic or nonallergic rhinitis. This causes an increase in airflow resistance upstream from the collapsible portion of the pharynx. As a result, the degree of negative collapsing pressure is increased on inspiration, rendering the pharynx more collapsible. Indeed, experimentally induced nasal obstruction can induce sleep-disordered breathing (Tanaka and Honda, 1989). Increased nasal airflow resistances due to allergic rhinitis can induce or worsen OSA and can be alleviated by intranasal steroids or spontaneous resolution of rhinitis (Kiely, 2004).

19 Review of Literature However, surgical correction of a deviated nasal septum does not consistently alleviate OSA, although it may reduce continuous positive airway pressure (CPAP) requirements in patients with severe OSA. Although nasal obstruction may contribute to upper airway collapsibility, data are insufficient to clarify its role in the pathogenesis of OSA (Kim, 2004). The significance of the combination of skeletal., and soft tissue factors in predisposing to upper airway obstruction is highlighted by observations in subjects with acromegaly, in whom prevalence of OSA is increased (Grunstein, 1991). In acromegaly, a dorsocaudal rotation of the mentum with posterior-cranial repositioning of the angle of the mandible causes retrodisplacement of an enlarged tongue (Hochban, 1999). Treatment of acromegaly may cause regression of some of the soft tissue changes (particularly the macroglossia), but because the skeletal., abnormalities are permanent, OSA often persists (Ip, 2001). Π-Other risk factors of osas A- physiological Factors: In addition to the Upper airway Anatomical Risk Factors described above that contribute to OSA pathogenesis, there are multiple other physiological variables that may impact OSA. Some of these components are described below and are illustrated schematically in. 1-REM Sleep: Hypopneas and apneas increase in duration and are associated with more pronounced hypoxemia during REM compared with non-rem sleep in OSA. Some patients have OSA only during REM sleep., REM

20 Review of Literature sleep is associated with decreased upper airway muscle tone, impaired genioglossus reflex responsiveness to negative pressure, and reduced chemosensitivity. These factors may worsen apnea during REM sleep. However, the arousal threshold appears higher during REM sleep, which would tend to reduce, not prolong, event duration, Further, Pcrit is similar during REM compared with non-rem sleep in patients with OSA, suggesting that upper airway anatomy is not further impaired in this sleep state (Schwartz et al., 1998). 2-Surface Tension: Surface tension of the liquid lining of the upper airway influences pharyngeal patency and changes in surface forces may perpetuate disease severity. Indeed, lining the upper airway with surfactant before sleep reduces apnea severity and improves the Pcrit in OSA (Kirkness et al., 2003). Patients with OSA appear to have increased surface forces acting on the upper airway despite similar salivary flow compared with healthy individuals. Further, the route of breathing during sleep appears to influence salivary flow and perhaps as a result may affect surface tension. Nasal breathing may reduce, and oral breathing may increase, surface tension forces (Verma et al., 2006). 3-Upper Airway Sensory Neuropathy/Impaired Sensory Processing: It has been proposed that the repeated mechanical trauma and/or hypoxemia associated with OSA may lead to sensory impairment of upper airway structures. Should this be the case, prolonged untreated OSA may perpetuate disease severity because of an impaired ability of the upper airway to respond to negative pharyngeal pressure.. Nonetheless, upper airway sensory function has been shown to be impaired in OSA during wakefulness (Nguyen et al., 2005).

21 Review of Literature B-The epidemiological risk factors for OSA include Genetic, obesity,gender and Aging 1-Genetic: Studies have clearly shown a common familial basis to the development of OSA (Mathur Douglas, 1995). This finding is true for both obese and nonobese patients with OSA. Studies using linkage analysis have provided initial insight into the potential link between specific areas of the genome and OSA pathogenesis (Patel, 2005). Anatomy (obesity, craniofacial structure) clearly have genetic underpinnings. Furthermore, traits such as the size of the upper airway soft tissue structures ventilatory control abnormalities and respiratory responses to resistive loading during sleep may also have a genetic basis (Larkin et al., 2006 & Polotsky and O'Donnell, 2007). Both hypercapnic and hypoxic responses are reduced in OSAS family members and both phenotypes are found to be highly heritable traits. Additional genetic effects on central and peripheral chemosensitivity, body fat and craniofacial or upper airway anatomy systematic approach to physical examination is recommended to avoid confusion. 1-Obesity: Although it is clear that obesity is a key risk factor for the development of OSA and modest reductions in weight lead to improvement in OSA severity (Peppard et al., 2000), Deposition of fat around the pharyngeal airway is likely to increase the collapsibility of the pharyngeal airway. Weight loss leads to important improvements in Pcrit.

22 Review of Literature Fat deposition around the abdomen leads to reductions in functional residual capacity, which would be predicted to reduce lung volume tethering effects on the upper airway. Low lung volumes are also associated with diminished oxygen stores, which would contribute to ventilatory control instability (high loop gain). Finally, obesity has been associated with functional impairment in upper airway muscles (Carrera et al., 2004). 3-Male Sex: Imaging studies have revealed that men have increased fat deposition around the pharyngeal airway and increase length of it as compared with women. So men have smaller retropalatal crosssectional area and higher compliance during sleep compared with women. There was no significant difference, however, after correction for body surface area. In addition, the pharyngeal airway is longer in postmenopausal as compared with premenopausal women. However, Hormonal differences between men and women have long been proposed to contribute to the increased male prevalence in OSA and to the propensity for women to develop OSA after menopause (Vgontzas et al., 2001). In addition to sexrelated changes in the apnea threshold, the ventilatory response to arousal from sleep is greater in men than women, suggesting that men may be more prone to cyclical breathing (Jordan et al., 2004; Huang et al., 2005; Huang et al., 2007 & Ronen et al., 2007). 4-Aging: The frequency of apnea increases with aging. However, the increase in prevalence appears to plateau after 65 years (Young et al.,

23 Review of Literature 2004) and when body mass index is controlled for, the severity appears to decrease with age (Wellman et al., 2007). Anatomic susceptibility to OSA due to deposition of fat around the pharynx with aging, independent of systemic fat. Similar to many upper airway reflexes, the genioglossus negative pressure reflex appears to deteriorate with aging. Indeed, these anatomic and physiological factors both likely contribute to increased upper airway collapsibility with aging (Eikermann et al., 2007).

24 Review of Literature Pathophysiology of OSAS: Despite progress in elucidating several aspects of its pathogenesis over the last 25 years, its etiology remains elusive. Progress is hampered by the occurrence of OSA only during sleep, making invasive and interventional studies difficult to perform while maintaining the sleep state. The critical pathophysiological feature of OSA is sleep-related collapse of the upper airway (UA) at the level of the pharynx. Essentially, pharyngeal collapse occurs when the normal reduction in pharyngeal dilator muscle tone at the onset of sleep is superimposed on a narrowed and/or highly compliant pharynx. This highlights the interaction of anatomic and neural state-related factors in causing pharyngeal collapse (Watanabe, 2002). The pathophysiological causes of OSA likely vary considerably between individuals. Important components other than upper airway anatomy likely include the ability of the upper airway dilator muscles to respond to respiratory challenge during sleep, the propensity to wake from increased respiratory drive during sleep (arousal threshold), the stability of the respiratory control system (loop gain), and the potential for state-related changes in lung volume to influence these factors. These various physiological traits have a role in the pathophysiology of obstructive sleep apnea (White, 2006). Pharyngeal Collapsibility: Compliance and critical closing pressure: In addition to reduced upper airway caliber, upper airway collapsibility is also increased in OSA patients. In general, upper airway collapsibility is a function of the balance of surrounding

25 Review of Literature tissue collapsing pressure, intraluminal pressure, and compliance of pharyngeal walls (Brown, 1985). Pharyngeal compliance is expressed as the change in volume or cross-sectional area per unit change in pressure and is an indicator of the ease with which an airway can be deformed. Because compliance is usually considered to reflect the passive properties of the tissues, it is difficult to quantify because of the difficulty in ensuring that UA muscle activation is not contributing to such measurements. Greater UA compliance is related to greater collapsibility of the UA in OSA patients than in control subjects (Kuna, 1988). Passive collapsibility of the UA has been assessed during natural or benzodiazepine-induced sleep and during muscular paralysis by vecuronium. Under these conditions, the UA is stabilized with CPAP. Passive UA collapse is induced by a sudden reduction in CPAP or application of negative pressure while nasal or pharyngeal pressure is recorded. The pressure at which the UA collapses (Isono, 1993). Upper Airway Dilator Muscle Activity and Reflex Responsiveness: During wakefulness, patients with OSA appear to compensate for an anatomically compromised upper airway through protective reflexes which increase upper airway dilator muscle activity to maintain airway patency. Accordingly, the genioglossus, the largest and most extensively studied upper airway dilator muscle in humans, has higher activity in patients with OSA compared with control subjects. One mechanism believed to be important in the pathogenesis of OSA relates to the interaction between pharyngeal anatomy and a diminished ability of the upper airway dilator muscles to maintain a patent airway during sleep (Mezzanotte et al., 1992).

26 Review of Literature In support of this hypothesis, muscle tone measured via multiunit EMG intramuscular electrodes of the genioglossus is reduced at sleep onset in healthy individuals and patients with OSA. Thus, whereas healthy individuals experience a loss of upper airway muscle tone at sleep onset and experience some degree of breathing instability (Trinder et al., 1992), an individual reliant on muscle tone due to an anatomic vulnerability will be particularly susceptible to developing OSA. Accordingly, hypopneas and apneas commonly occur at the transition from wakefulness to sleep in OSA. As is discussed below, each event is typically associated with a cortical arousal such that the patient with OSA cycles between wakefulness and sleep, making it difficult to achieve deeper stages of sleep. Unlike the transition to sleep, slow wave sleep is associated with increased, not decreased, upper airway dilator muscle activity. Thus, when patients are able to achieve slow wave sleep, increased upper airway dilator muscle activity may be one important factor contributing to the improvement in apnea severity that is commonly observed in this sleep stage. Alternatively, patients with apnea may be able to enter slow wave sleep only when muscle activity is increased and breathing is already stabilized (Mezzanotte et al., 1996 and Worsnop et al., 1998). Mechanistically, in addition to central respiratory drive, the genioglossus is importantly modulated by locally mediated (i.e., in the upper airway) mechanoreceptive reflex mechanisms that respond to negative pharyngeal pressure. One such mechanism is the genioglossus negative pressure reflex, whereby the muscle is activated in response to rapid changes in negative intrapharyngeal pressure (i.e., pressures that are subatmospheric or suction pressure) (Horner et al., 1991). Consistent with the nature of OSA being a state-related disease, the genioglossus

27 Review of Literature negative pressure reflex has been shown to be diminished during nonrem sleep in healthy individuals (Wheatley et al., 1993 & Pillar et al., 2001). However, more recent data have demonstrated maintenance of genioglossus reflex activation in non-rem sleep, particularly in the supine posture when gravitational collapsing effects on the upper airway are maximam. The identification of a secondary state-dependent suppression component to this reflex arc has raised the possibility that more pronounced reflex inhibition rather than a loss of excitation may mediate diminished pharyngeal reflex responses during sleep (Ecker et al., 2007). Advances in our understanding of the neuroanatomy of the genioglossus negative pressure reflex and hypoglossal motor nucleus inputs from rat studies have highlighted the extensive presence of inhibitory inputs to the genioglossus muscle (Chamberlin et al., 2007). Nonetheless, although genioglossus muscle responsiveness may be impaired during sleep compared with wakefulness, it is clear that the muscle does respond to sustained negative pressure and potentially hypercapnia, particularly when combinations of stimuli are provided. However, there appears to be substantial interindividual variability in the effectiveness of these compensatory responses to restore airflow during respiratory loading in sleep (Jordan et al., 2007). To further advance our understanding of pharyngeal muscle control and its role in OSA pathogenesis, single motor unit recording techniques have been employed to assess genioglossus muscle activity in humans. This technique is based on high-frequency sampling and allows sorting of individual motor units to gain insight into their unique characteristics and regulation. Although these studies are in their infancy, they have

28 Review of Literature highlighted the heterogeneity of the genioglossus muscle and provide a powerful tool for studying the neural control of muscle activity (Saboisky et al., 2006). It is hoped that, by combining neuroanatomic knowledge from animal models with sensitive neurophysiological techniques in humans, novel therapeutic targets to increase muscle activity may ultimately be identified for some patients with OSA. Although such approaches may lead to reduced severity of OSA for some patients, as is discussed below, given the heterogeneity of OSA pathogenesis such an approach will likely not resolve sleep-disordered breathing for all patients. Nonetheless, there is evidence to suggest that novel training exercises of upper airway muscles may lead to some improvement in sleep-disordered breathing. However, on the basis of the state dependence of OSA, muscle training during wakefulness is unlikely to have major effects on airway patency during sleep unless the increased muscle activity/efficiency is maintained during sleep (Randerath et al., 2004). Arousal from Sleep: Arousal from sleep at the cessation of a hypopnea or an apnea has long been believed to be an important protective mechanism for airway reopening (Phillipson and Sullivan, 1978). In fact, most respiratory events are associated with cortical arousal and more severe events result in longer arousals. However, work by Younes has provided insight into the functional role of arousal from sleep in OSA and challenged the notion that it is essential for airway reopening. In studying the response to experimentally induced transient continuous positive airway pressure (CPAP) reductions in patients with OSA, Younes noted that inspiratory flow increased in 22% of instances before arousal and was restored in

29 Review of Literature 17% of trials in the absence of arousal (Younes, 2004). More recently, Jordan and colleagues conducted a study to examine the mechanisms underlying these arousal-free restorations of airflow. Transient pressure reductions for up to 5 minutes resulted in increases in genioglossus muscle activity and changes in duty cycle. These compensatory responses were similar between patients with OSA and healthy individuals. However, patients with OSA were less able to restore ventilation without cortical arousal than were healthy individuals given stimuli of similar magnitude (Jordan et al., 2007). The findings that patients with OSA are able to restore ventilation in the face of respiratory loading without cortical arousal at least some of the time, albeit to a lesser extent than healthy individuals, raises the possibility that some patients may be able to maintain a patent airway during sleep if they are able to remain asleep for a sufficient duration to recruit compensatory mechanisms. For example, because combinations of stimuli such as carbon dioxide and negative pressure can activate upper airway dilator muscles during sleep, delaying of arousals may be beneficial if it allows sufficient accumulation of respiratory stimuli to restore pharyngeal patency. Should this be the case, strategies to prevent arousal from sleep (increase the arousal threshold) are likely to be most beneficial in patients who awaken easily (low arousal threshold) to respiratory loads during sleep. However, increasing the arousal threshold in patients with a preexisting high arousal threshold, for example, in patients with severe sleep-disordered breathing, may be deleterious because of worsening of blood gas abnormalities (White, 2006 & Younes et al., 2007).

30 Review of Literature Most of the available evidence suggests that the level of pleural pressure, generated by respiratory effort regardless of the stimulus (e.g., hypoxia, hypercapnia, and respiratory loading), is likely to be the key trigger for inducing arousal from non-rem sleep (Gleeson et al., 1990). Experimentally, the arousal threshold is measured as the minimal esophageal pressure (or pressure at the level of the epiglottis, which is likely to be similar during airway occlusion) generated on the breath preceding arousal during a respiratory load or occlusion. depicts quantification of the arousal threshold, in this instance during airway occlusion during a naturally occurring apnea. Although there is wide interindividual variability, patients with OSA tend to have an impaired arousal response to airway occlusion (more negative pressure required or a higher arousal threshold) than control subjects. Treating OSA with CPAP tends to lower the arousal threshold. These findings suggest that OSA (e.g., sleep fragmentation, hypoxia, and repeated airway obstruction) rather than an inherent abnormality in the arousal threshold is responsible for the impaired arousal responses in patients with OSA (Haba-Rubio et al., 2005). When initiated, arousal from sleep is associated with heightened upper airway dilator muscle activity for an equivalent level of negative pharyngeal pressure during sleep and a brisk ventilatory response Although these changes are beneficial in rapidly restoring airflow and reversing oxygen desaturation/hypercapnia, as is discussed in the following section, they can also destabilize breathing and perpetuate apnea severity (Jordan et al., 2003).

31 Review of Literature Ventilatory Control Stability: A typical feature of OSA is the cyclical breathing pattern that develops, whereby the patient oscillates between obstructive breathing events (sleep) and arousal (wakefulness) Further, obstructive events tend to occur during periods of low respiratory drive. Thus, ventilatory control stability is believed to be an important contributor to OSA pathogenesis. Ventilatory control stability can be described using the engineering concept loop gain. Essentially, loop gain is a term used to describe the stability of a system controlled by feedback loops. In the context of ventilatory control, loop gain refers to the stability of the respiratory system and how responsive the system is to a perturbation to breathing (e.g., arousal). In other words, loop gain can be considered as the propensity for the ventilatory control system to develop cyclical fluctuations in ventilatory output (as seen in periodic breathing). There are two principal components to loop gain: controller gain and plant gain. As it relates to respiratory control, controller gain refers to the chemoresponsiveness of the system (i.e., hypoxic and hypercapnic ventilatory responses). Plant gain reflects primarily the efficiency of CO2 excretion (i.e., the ability of a given level of ventilation to excrete CO2). A third factor, known as mixing gain, appears to be less crucial, but is a function of circulatory delay as well as hemoglobin binding of O2 and CO2. Mixing gain tends to be fairly constant, although circulatory delays may make mixing gain more clinically relevant in patients with congestive heart failure (Wellman et al., 2004). The physical separation of the sensors and effectors makes the ventilatory feedback control system vulnerable to instability. An inherently high loop gain system is unstable (i.e., robust ventilatory

32 Review of Literature response to a respiratory stimulus) compared with a low loop gain system (i.e., dampened ventilatory response to an equivalent respiratory stimulus). A commonly used analogy is the regulation of room temperature, whereby temperature will be prone to oscillation in a situation where there is a particularly sensitive thermostat and an overly powerful heater (i.e., high loop gain). Techniques have been developed to measure loop gain of the respiratory system, such as the proportional assist ventilation (PAV) technique. Studies using PAV have demonstrated that patients with OSA do in fact have an elevated loop gain and suggest that ventilatory instability is an important mechanism contributing to sleep-disordered breathing (Stanchina et al., 2007). Debate exists regarding how elevated loop gain may affect the propensity for apnea. There are two key potential mechanisms that are likely to be important, although neither is definitively proven. First, elevated loop gain would be expected to increase oscillations from the brainstem central pattern generator. One would predict that pharyngeal obstruction occurs when ventilatory motor output is at its nadir (i.e., when neural output to the upper airway muscles is low). Second, elevated loop gain may also increase the ventilatory response to arousal, which may drive PaCO2 below the apnea threshold during subsequent sleep. Obstructive or central apnea could then occur depending on the prevailing upper airway mechanics. Thus, further work is required in this area (Stanchina et al., 2007). Lung Volume: The interaction between pharyngeal patency and lung volume is believed to be an important contributor to OSA pathogenesis. Indeed, upper airway mechanics can be modulated by changes in lung volume

33 Review of Literature during wakefulness and sleep in healthy individuals.further, demonstrated that across the range from residual volume to total lung capacity there is a lung volume dependence on upper airway crosssectional area measured during wakefulness. In addition, the lung volume dependence appears to be more pronounced in patients with OSA compared with control subjects. However, studies during wakefulness are confounded by behavioral influences because a maximal inhalation to total lung capacity is likely to activate upper airway muscles behaviorally as well. During sleep, upper airway resistance increases as lung volume is reduced. Increasing end-expiratory lung volume decreases airway collapsibility in healthy control subjects and improves sleep-disordered breathing in patients with OSA (Kay et al, 1996). While the aforementioned studies demonstrate that changes in lung volume are capable of modulating upper airway patency in OSA, the underlying mechanisms have not been well defined in humans. One likely mechanism, which has been clearly demonstrated in animal models (Kairaitis et al., 2007), is the concept of a loss of caudal traction on upper airway structures during decreased lung volume. Briefly, when lung volume is reduced there is a displacement of the diaphragm and thorax toward the head. This movement results in a loss of caudal traction on the upper airway, yielding a more collapsible airway. Data obtained by examining the interaction between passive pharyngeal airway and lung volume independent of neuromuscular factors in patients with sleepdisordered breathing suggest that similar mechanisms may contribute to OSA pathogenesis (Tagaito et al., 2007).

34 Review of Literature Diagnosis of OSAS Clinical features: History of Present Illness General issues in the presentation would be the age of onset of symptoms as well as some consideration of the trajectory of illness severity. Some of these features are the following symptoms: Sleepiness: Sleepiness is very common in sleep apnea patients: 38% to 51% in one epidemiological study and 47% to 73% in a sleep clinic population (Chervin, 2000). Despite this it is not associated with sleep apnea in clinical studies. This is in large part due to difficulty in differentiating sleep from fatigue. In a study of sleep apnea patients perception of their problems, lack of energy, tiredness, and fatigue while decreasing performance were more prevalent complaints than sleepiness (Kapur et al., 2005). One explanation for decreasing performance in sleep deprivation is the occurrence of microsleep. Microsleep is defined as brief (several seconds) runs of theta or delta activities that break through the otherwise beta or alpha EEG of waking. It has been seen to increase with sleep deprivation. In studies in which polysomnography is recorded simultaneously, microsleep impairs continuity of cognitive function and occurs prior to performance failure. However, the occurrence of microsleep has not been shown in most instances of polysomnographic correlated performance failure. Other explanations for performance

35 Review of Literature impairments include sensory perceptual impairments such as the development of visual neglect phenomena (Desseilles et al., 2008). Assessment of daytime sleepness through Epworth Sleepiness Scale (ESS): it is a questionnaire intended to measure daytime sleepiness {Murray Johns ) (Table 1). the following scale is used to choose the most appropriate number for each situation: 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Situation Sitting and reading Watching TV Sitting inactive in a public place (e.g. a theater or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in traffic Chance Of Dozing

36 Review of Literature The score obtained by adding the numbers leads to a total: average score, normal population sleep specialist advice recommended (Murray Johns ). Snoring: Snoring is extremely common in sleep apnea patients and its absence should make OSA less likely (Viner et al., 1991). In one study only 6% of patients with OSA did not report snoring. Keep in mind however, that many patients have misperceptions about their snoring and tend to underestimate it. Some studies have shown that a report of loud habitual snoring strengthens by seven-fold the statistical association with sleep apnea and snoring. Witnessed apneas are relatively specific for sleep apnea, but have a low sensitivity (Young et al., 2002). Insomnia: Insomnia complaints are highly prevalent in OSA (Krell and Kapur, 2005), reported that; Fifty-five percent of patients being referred for possible evaluation of OSA were noted to have complaints of insomnia, with difficulties maintaining sleep (38.8%) being more common than difficulties initiating sleep (33.4%) or early morning awakenings (31.4%). Despite the overall high prevalence of insomnia complaints in this study population, insomnia was more common in patients without rather than with significant sleep-disordered breathing (81.5% with AHI < 10 vs. 51.7% with AHI > 10) The high prevalence of insomnia complaints may be attributable to the fact that the sleep disruption associated with OSA may be perceived as insomnia, or

37 Review of Literature perhaps such patients with insomnia and OSA are more symptomatic, thus more likely to seek medical attention. Weight gain: Weight gain increases the probability of sleep apnea. One large population based study found a 10% weight gain and predicted a 32% increase in AHI. This translated to a six-fold increase in the odds of developing (moderate-to-severe) sleep apnea (Peppard et al., 2000). Inversely, a decrease in weight leads to an improvement in sleep apnea. Studies in bariatric surgery patients show a dramatic improvement in RDI after weight loss (Rasheid et al., 2003; Buchwald et al., 2004). One screening tool is the Berlin questionnaire, which is a simple and used to classify subjects who are at high risk and low risk for OSA by identifying snoring behavior, daytime sleepiness, obesity, and hypertension. BERLIN QUESTIONNAIRE The questionnaire consists of 3 categories related to the risk of having sleep apnea. Patients can be classified into High Risk or Low Risk based on their responses to the individual items and their overall scores in the symptom categories (Table 2).

38 Review of Literature CATEGORY 1 1. Do you snore? a. Yes b. No c. Don t know If you snore: 2. Your snoring is: a. Slightly louder than breathing b. As loud as talking c. Louder than talking d. Very loud can be heard in adjacent rooms 3. How often do you snore a. Nearly every day b. 3-4 times a week c. 1-2 times a week d. 1-2 times a month e. Never or nearly never 4. Has your snoring ever bothered other people? a. Yes b. No c. Don t Know CATEGORY 2 6. How often do you feel tired or fatigued after your sleep? a. Nearly every day b. 3-4 times a week c. 1-2 times a week d. 1-2 times a month e. Never or nearly never 7. During your waking time, do you feel tired, fatigued or not up to par? a. Nearly every day b. 3-4 times a week c. 1-2 times a week d. 1-2 times a month e. Never or nearly never 8. Have you ever nodded off or fallen asleep while driving a vehicle? a. Yes b. No If yes: 9. How often does this occur? a. Nearly every day b. 3-4 times a week 5. Has anyone noticed that you c. 1-2 times a week quit breathing during your sleep? d. 1-2 times a month a. Nearly every day e. Never or nearly never b. 3-4 times a week c. 1-2 times a week CATEGORY 3 d. 1-2 times a month e. Never or nearly never 10. Do you have high blood pressure? Yes No Don t know (Netzer et al., 1999)

39 Review of Literature Categories and scoring: Category 1: items 1, 2, 3, 4, 5. Item 1: if Yes, assign 1 point Item 2: if c or d is the response, assign 1 point Item 3: if a or b is the response, assign 1 point Item 4: if a is the response, assign 1 point Item 5: if a or b is the response, assign 2 points Add points. Category 1 is positive if the total score is 2 or more points Category 2: items 6, 7, 8 (item 9 should be noted separately). Item 6: if a or b is the response, assign 1 point Item 7: if a or b is the response, assign 1 point Item 8: if a is the response, assign 1 point Add points. Category 2 is positive if the total score is 2 or more points Category 3 is positive if the answer to item 10 is Yes OR if the BMI of the patient is greater than 30kg/m2 (BMI must be calculated. BMI is defined as weight (kg) divided by height (m) squared, i.e., kg/m2). High Risk: if there are 2 or more Categories where the score is positive Low Risk: if there is only 1 or no Categories where the score is positive Additional question: item 9 should be noted separately. Nocturia: Frequent awakening from sleep to urinate is common in sleep apnea patients. One retrospective study found a prevalence of 49% in sleep apnea patients (Hajduk et al., 2003) and others have noted frequent nocturia is related to sleep apnea severity (Hajduk et al., 2003; Fitzgerald et al., 2006). Past Medical History:

40 Review of Literature OSA will coexist with other sleep disorders. A retrospective analysis of 643 OSA patients found that 31% had another sleep disorder: 14.5% had poor sleep hygiene and 8.1% had PLMD (Scharf et al., 2005). In two other studies more than 50% of sleep apnea patients complained of insomnia (Krell and Kapur, 2005). Sleep apnea is not only associated with cardiovascular disease but may directly contribute to its pathogenesis. It was present in 38% of hypertensive subjects in one study (Worsnop et al., 1998). Several trials found a small but significant improvement in hypertension with sleep apnea treatment. Others suggest that the prevalence of sleep apnea in patients with CAD, postmyocardial infarction, CHF, and poststroke to be 50%. Results from the Sleep Heart Health Study show increasing odds of self-reported heart failure, stroke, and CAD in subjects with a high AHI (Shahar et al., 2001; Pepperell et al., 2002 & Becker et al., 2003). Several studies have found that sleep apnea is independently associated with glucose intolerance and insulin resistance. They found improvement in glucose control in patients treated for sleep apnea (Punjabi et al., 2002; Punjabi et al., 2004). Sleep apnea in the setting of pulmonary diseases is called the overlap syndrome. Chronic obstructive pulmonary disease is the most common of these, but has a prevalence in the sleep apnea population similar to that of the general population Arterial hypertension is another disease but is much less common and the prevalence of sleep apnea in these patients is not well studied (Atwood et al., 2004 & Bednarek et al., 2005).

41 Review of Literature The occurrence of sleep disturbances during pregnancy is well documented. Although specific sleep disorders tend to emerge during different stages of pregnancy, the third trimester appears to be the most vulnerable. Of special attention are those women who gain excessive weight during pregnancy. Thus, during routine perinatal obstetrical care, the sleep history should be periodically revisited (Sahota et al., 2003). Social History: Sleep apnea significantly worsens after heavy alcohol ingestion (Taasan et al., 1981). The Wisconsin Sleep Cohort Study found current smokers to have an increased risk of having moderate sleep apnea compared to nonsmokers Some proposed mechanisms include increased nasal resistance due to edema, and reduced hypoglossus motor nerve activity (Wetter et al., 1994). Family History: Redline et al., (1995) found that there is a familial aggregation to sleep apnea. Families with an index case of sleep apnea had a higher prevalence of sleep apnea than in those without (21% vs. 9%, p 0.02) and risk increased with additional affected members. The Physical Examination For Sleep Apnea: A sleep physical examination is directed at modifying the probability of sleep disordered breathing based on the history, looking for evidence of associated or complicating disease, and excluding other potential causes for neurologic or cardiovascular symptoms. A broader examination incorporating many of the

42 Review of Literature other organ systems should be employed when considering other sleep disorders that may be caused by. can be either too thin or too heavy), and their position (relative population-based percentile standing) on age-appropriate growth charts. A thorough examination would include mention of the patient s general appearance and craniofacial characteristics such as midface hypoplasia, micrognathia. Flemons et al (1994) found that the neck circumference, history of hypertension, history of snoring, and history of night-time choking or gasping were all independent predictors of OSAS. The adjusted neck circumference screening score (ANCSS) includes these variables and is believed to be an effective way of predicting the probability of an individual having OSAS. The authors noted that the most important factor was neck circumference. It was equivalent in its predictive effect to a combination of other factors, such as body mass index (BMI), age, or gender. None of these parameters are perfect, but they are used to identify which patients are appropriate candidates for polysomnography (PSG). Most importantly, none of these parameters are indicated to be predictive of treatment success. Although NC shows a strong correlation with both overweight and obesity, it is reasonable to consider it as a screening test. Men with NC < 37 cm and women with NC < 34 cm do not require additional evaluation. Patients above these levels require a more comprehensive evaluation of their overweight or obesity Flemons et al (1994).

43 Review of Literature Nasal Function: Nasal obstruction has been implicated as a potential cause of sleep apnea. It can lead to higher inspiratory upper airway pressures and increased collapsibility of pharyngeal walls. Also, it appears to predispose to mouth breathing and the downward and backward displacement of the mandible, which may worsen airway obstruction at the level of the base of the tongue. Nasal resistance, as measured by posterior rhinometry, was significantly higher in patients with sleep apnea combination of nasal obstruction and a high Mallampati score (3 or 4) (fig 6) are associated with an increased risk for the diagnosis of sleep apnea (Liistro et al., 2003 & Rombaux et al., 2005).

44 Review of Literature Figure (6): Mallampati classification system based on visualization of posterior oropharyngeal structures. Class 1, soft palate, fauces, uvula, anterior and posterior pillars visible; Class 2, soft palate, fauces and uvula visible; Class 3, soft palate and base of uvula visible; Class 4, soft palate not visible (American Academy of Sleep Medicine,2001). The external nasal valve comprises the columella, the nasal floor, and the nasal rim [inferior border of the lower lateral alae nasi (nasal cartilage)], which normally is dilated by the nasalis muscle during inspiration. Collapse of the nasal rim upon

45 Review of Literature inspiration through the nose alone, is also often a sign of OSAassociated nasal resistance) Rombaux et al., 2005) Pharyngeal and Craniofacial Features: Pharyngeal and craniofacial morphology play an important role in the etiology of sleep apnea. Some anatomical variants result in obstruction a crowded during oropharyngeal sleep. Many space clinical and studies predispose have to taken different measures of pharyngeal and craniofacial morphology and found associations between them and the presence of sleep apnea. Their utility however, has been notably impaired by their lack of simplicity and practicality at the bedside. One measure used in the assessment is the Mallampati score (Fig.6). Designed originally by anesthetists to grade intubation difficulty, Scalloping or dental impressions at the edge of the tongue may indicate the presence of an enlarged tongue that habitually presses against the teeth. Retrognathia, micrognathia, and overbite are craniofacial features that capture jaw factors that are associated with a restricted posterior pharynx. These are recognized qualitatively by noting the relative size of the jaw to the maxilla, forward protrusion of the upper teeth over the lower teeth, and absent lower teeth that were surgically removed due to crowding. Quantitative measures of these features are typically obtained by cephalometric radiographs and may be useful in modifying disease probability (Tsai et al., 2003). Neuromuscular disorders, such as myotonic dystrophy, can be associated with chronic obstructive hypoventilation from a combination

46 Review of Literature of oropharyngeal muscle weakness that leads to airway collapse and hypoventilation from diminished respiratory muscle excursion (Kotagal et al., 2003). Laboratory Testing: Nocturnal polysomnography is the gold standard for diagnosing obstructive sleep apnea. In this technique, multiple physiologic parameters are measured while the patient sleeps in a laboratory. Typical parameters in a sleep study include eye movement observations (to detect rapid-eye-movement sleep), an electroencephalogram (to determine arousals from sleep), chest wall monitors (to document respiratory movements), nasal and oral airflow measurements, an electrocardiogram, an electromyogram (to look for limb movements that cause arousals) and oximetry (to measure oxygen saturation). Apneic events can then be documented based on chest wall movement with no airflow and oxyhemoglobin desaturations. EEG changes during stage 1: The normal subject on closing his eyes will show a dominant rhythm in the 8-13 HZ range (the alpha rhythm). As the subject drowses the alpha rhythm present shows a fall in the amount, and amplitude and may slow slightly. Occasionally it may stops abruptly, and then replaced by a pattern of mixed low voltage components in the fast ( 14 HZ) and theta (4-7 HZ) ranges and a small amount of underlying delta (0.5-3 HZ) range (Carskadon and Dement, 1989) (Fig 2). AASM Manual, 2007 Rules:

47 Review of Literature A. In subjects who generate alpha rhythm, score stage N1 if alpha rhythm is attenuated and replaced by low amplitude, mixed frequency activity for more than 50% of the epoch. B. In subjects who do not generate alpha rhythm, score stage N1 commencing with the earliest of any of the following phenomena: 1) Activity in range of 4-7 Hz with slowing of background frequencies by 1 Hz from those of stage W. 2) Vertex sharp waves. 3) Slow eye movements. (Iber et al., 2007) Stage 2: During this stage the subject lies quietly and a more intense stimulus is required to produce an arousal, while the same stimulus that produced arousal from stage 1 sleep will often result in an evoked complex but no awakening in stage 2 sleep. It occupies the greatest amount of total sleep time in the normal young adult about 45-55% (Carskadon and Dement, 1989) EEG changes during stage 2: This stage is characterized by appearance of k-complexes (a sharp negative wave immediately followed by abroader, high voltage positive component) and sleep spindles (short bursts of Hz activity) associated with a pattern of slow activity in the theta and delta ranges. At first this slow activity is of relatively low amplitude which in turn shows a gradual increase (Carskadon and Dement, 1989) (Fig 7).

48 Review of Literature Theta wave K complex Delta wave Figure (7): Characteristic EEG activity of each of the four stages of NREM sleep (Carskadon and Dement, 2005). AASM Manual, 2007 Rules: The following rule defines the start of a period of stage N2 sleep: Begin scoring stage N2 (in absence of criteria for N3) if 1 or both of the following occur during the first half of that epoch or the last half of the previous epoch: (Fig 3). One or more K complexes unassociated with arousals. One or more trains of sleep spindles. Note: Continue to score stage N1 for epochs with arousal-associated K complexes but no spontaneous K complexes or sleep spindles For the purposes of scoring N2 sleep, arousals are defined according to arousal rule (which is an abrupt shift of EEG frequency including alpha, theta, and /or frequencies greater than 16 hz (but not spindle) that last 3 second, with at least 10 seconds of stable sleep preceding the change.)

49 Review of Literature The following rule defines continuation of a period of stage N2 sleep: Continue to score epochs with low amplitude, mixed frequency EEG activity without K complexes or sleep spindles as stage N2 if they are preceded by a) K complexes unassociated with arousals or b) sleep spindles. The following rule defines the end of a period of stage N2 sleep: End stage N2 sleep when 1 of the following events occurs: Transition to stage W. An arousal (change to stage N1 until a K complex unassociated with an arousal or a sleep spindle occurs). A major body movement followed by slow eye movements and low amplitude mixed frequency EEG without nonarousal associated K complexes or sleep spindles (score the epoch following the major body movement as stage N1; score the epoch as stage N2 if there are no slow eye movements; the epoch containing the body movements is scored. Transition to stage N3. Transition to stage R.

50 Review of Literature Fig (8): Transition between stage N1 and stage N2 according to AASM Manual, 2007 rules. (Iber et al., 2007) Stage 3: This stage is defined by the presence in the EEG for more than 20% and less than 50% of an epoch of slow activity at less than 2 HZ and greater than 75 uv in amplitude peak-to-peak (delta wave) (Rechtschaffen and Kales, 1968) (Fig. 2). This slow activity is bisynchronous and generalized. Not infrequently its amplitude is more marked anteriorly. Stage 3 sleep usually lasts only a few minutes in the first cycle and is transitional to stage 4 as more and more high voltage slow wave activity occurs (Carskadon and Dement, 1989). AASM Manual, 2007 Rules: Score stage N3 when 20% or more of an epoch consists of slow wave activity, irrespective of age. (Iber et al., 2007)

51 Review of Literature Stage 4: It is characterized by the presence of high voltage slow activity at less than 2 Hz and of 75 uv amplitude peak-to-peak or more which is present for greater than 50% of the epoch. Stage 4 non-rem sleep occupies 10-15% of the total sleep time in young adult. An incrementally larger stimulus is generally required to produce an arousal from stages 3 and 4 sleep than from stage 1 or 2 sleep (Gillard and Blois, 1981) (Fig. 2). Stage REM: A REM sleep period is characterized by three main features the presence of rapid eye movements (REMS), a low amplitude mixed frequency EEG, and a striking reduction of muscle tone in the submental EMG. Saw-toothed waves are commonly seen in stage REM, usually just before and overlapping the onset of REM (Rechtschaffen and Kales, 1968). The atonia of REM sleep has been clearly shown to involve predominantly the postural muscles not only of the neck but the accessory respiratory muscles and the intercostal muscles as well (Duron and Marlot, 1980). This atonia does not appear to involve the diaphragm and the extra-ocular muscles (Siegel, 1989). Dreaming is most often associated with REM sleep. Loss of muscle tone and reflexes likely serves an important function because it prevents an individual from acting out their dreams or nightmares while sleeping. Approximately 80 percent of vivid dream recall results after arousal from this stage of sleep. REM sleep may also be important for memory consolidation (Bader et al., 2003).

52 Review of Literature AASM Manual, 2007 Rules: A. Score stage R sleep in epochs with all the following phenomena: a. Low amplitude, mixed frequency EEG. b. Low chin EMG tone. c. Rapid eye movements. B. The following rule defines the continuation of a period of stage R sleep: Continue to score stage R sleep, even in the absence of rapid eye movements, for epochs following I or more epochs of stage R as defined in A above, if the EEG continues to show low amplitude, mixed frequency activity without K complexes or sleep spindles and the chin EMG tone remains low. C. The following rule defines the end of a period of stage R sleep: 1) Stop scoring stage R sleep when 1 or more of the following occur: a. There is a transition to stage W or N3. b. An increase in chin EMG tone above the level of stage R is seen and criteria for stage NI are met. c. An arousal occurs followed by low amplitude, mixed frequency LEG and slow eye movements (score as stage N1; if no slow eye movements and chin EMG tone remains low, continue to score as stage R). d. A major body movement followed by slow eye movements and low amplitude mixed frequency EEG without non-arousal associated K complexes or sleep spandles (score the epoch following the major body movement as stage N1; if no slow eye movements and the EMG toneremains low, continue to score as stage R; the epoch containing the body movement is scored (Fig. 4).

53 Review of Literature e. One or more non-arousal associated K complexes or sleep spindles are present in the first half of the epoch in the absence of rapid eye movements, even if chin EMG tone remains low (score as stage N2) (Fig. 5). D. Score epochs at the transition between stage N2 and stage R as follows: 1) In between epochs of definite stage N2 and definite stage R, score an epoch with a distinct drop in chin EMG in the first half of the epoch to the level seen in stage R as stage R if all of the following criteria are met, even in the absence of rapid eye movements: a. Absence of non-arousal associated K complexes. b. Absence of sleep spindles 2) In between epochs of definite stage N2 and definite stage R, score an epoch with a distinct drop in chin EMG in the first half of the epoch to the level seen in stage R as stage N2 if all of the following criteria are met: a. Presence of non-arousal associated K complexes or sleep spindles. b. Absence of rapid eye movements 3) In between epochs of definite stage N2 with minimal chin EMG tone and definite stage R without further drop in chin EMG tone, score epochs as stage R if all of the following are met, even in the absence of rapid eye movements: (Fig. 6) a. Absence of non-arousal associated K complexes. b. Absence of sleep spindles

54 Review of Literature Fig (9): Transition between stage R to stage N1 according to AASM Manual, 2007 rules. Fig (10): Transition between stage R to stage N1 or stage N2 according to AASM Manual, 2007 rules.

55 Review of Literature Fig (11): Transition between stage N1 or stage N2 to stage R according to AASM Manual, 2007 rules. (Iber et al., 2007) Typically, a respiratory disturbance index (RDI) is calculated and expressed as the number of abnormal respiratory events per hour of sleep. Some sleep laboratories use an RDI of 20 episodes per hour as the cutoff point to consider continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea, although the degree of symptoms is an important consideration regardless of the RDI. Multiple sleep latency test: A multiple sleep latency test may also be performed to assess the level of daytime sleepiness.25 The average adult requires 10 or more minutes to fall asleep during the day. A mean sleep latency of less than 5 minutes is considered abnormal. More aggressive treatment of obstructive sleep apnea might be considered in a patient with a relatively low RDI who exhibits significant daytime sleepiness (Carskadon et al., 1986).

56 Review of Literature Radiological methods: Diverse obstruction methods in OSA have been patients. used No to identify technique sites is of without methodological problems, ranging from the invasiveness of the procedures with concomitant sleep disruption (eg, endoscopy and catheters) to viewing exposure (eg, time fluoroscopy limitations and CT secondary scanning). to radiation Given these limitations, the precise localization of the sites of obstruction in patients with OSA may not be possible using current techniques. Nevertheless, the majority of studies, irrespective of technique, indicate that the primary site of obstruction is at the level of the oropharynx, although extensions to the laryngopharynx are frequently observed. Early investigations confined the site of obstruction in OSA patients to one particular location, whereas more recent studies have demonstrated multiple sites of obstruction within the same individual (Rama et al., 2002). Technologic advances in the methods used to detect the sites of obstruction in OSA patients have demonstrated that the UA is more dynamic than originally thought. The variable sites of obstruction imply a complex underlying pathogenesis of UA obstruction that is affected by many factors, including neck anatomy, adipose tissue distribution, anesthetics, sleep stage, and a variety of other components that are still unknown and collectively result in varying types of obstructions within the same individual.

57 Review of Literature A number of investigators have advocated localizing a site of obstruction as a means to support a given surgical procedure, such as a uvulopalatopharyngoplasty. The logic of this endeavor is essentially flawed, given the dynamic nature of the UA. The site of obstruction in a given OSA patient is as unique as his or her fingerprints, and efforts to advocate one surgical procedure for a single point of obstruction are unsound. Additional studies precisely characterizing the dynamic obstructions in OSA patients would be interesting. These investigations should include larger samples of patients, the use of anatomic nomenclature based on that in Grays Anatomy (Anil et al., 2002). Magnetic Resonance Imaging: MRI may be the best current mode of imaging for assessment of the upper airway and surrounding soft tissue and craniofacial structures (Figs. 1 4) Advantages of MRI include that it: (i) achieves high resolution images of the upper airway and soft tissue; (ii) provides precise and accurate measurements of the upper airway and surrounding tissue; (iii) obtains multiplanar images in the axial, sagittal, and coronal planes; (iv) permits volumetric data analysis reconstruction images of the including upper airway three-dimensional and surrounding structures; (v) permits state-dependent imaging; and (vi) avoids radiation exposure allowing for repeat measurements (Rodenstein et al, 1990 & Ciscar et al., 2001). The shortcomings of MRI include that it: (i) is costly and not widely available; (ii) cannot be performed on patients with met allic implants such as pacemakers; (iii) has noise related to the machine that can be disturbing to sleep; and (iv) is difficult to perform in patients with

58 Review of Literature claustrophobia and morbid obesity. Nonetheless, MRI studies have advanced our understanding of the pathophysiology of OSA as well as the mechanisms underlying effective treatments such as weight loss, CPAP, oral appliances, and upper airway surgery (Ryan et al., 1991; Schwab et al., 1995). The advent of ultrafast MRI techniques has provided multiple images at multiple sites with sufficient image quality and temporal resolution to allow a dynamic assessment of the pharyngeal musculature (Schwab, 1998; Jager, 1998; Ciscar et al., 2001). Volumetric MRI appears to be a powerful tool to assess and measure anatomic risk factors for OSA. Schwab et al (2003) demonstrated that the volume of upper airway soft tissue structures is enlarged in patients with sleep apnea, even after controlling for volume of the parapharyngeal fat pads (Fig. 5). Furthermore, the volume of the tongue and lateral pharyngeal walls were shown to be particularly important independent risk factors for sleep apnea (Schwab et al., 2003). Magnetic resonance imaging (MRI) has become an established method for the in vivo quantification of fat tissue. Fat has a relatively short T1 relaxation time, so fatty tissue has a higher intensity than other soft tissues in T1 weighted spin echo MRI images. The availability of this technique has prompted a number of studies which have attempted to clarify the relationship between obesity and upper airway obstruction at a detailed anatomical level (Suratt et al., 1987; Horner et al., 1989 and Shelton et al., 1993).

59 Review of Literature Figure (12) A representative T1-weighted spin echo magnetic resonance axial image in the RP region of a subject during wakefulness. The important anatomic structures are indicated. Note that fat is white on magnetic resonance imaging (Trudo FJ etal., 1998). Computed Tomography: CT is a noninvasive technique that permits a thorough evaluation of the entire upper airway. CT techniques employed to study the upper airway include standard axial CT images with the option to three-dimensionally reconstruct the upper airway structures (Ryan et al., 1991 and Li et al., 2003), electron beam CT that permits dynamic evaluation, and helical CT scanners that have the ability to provide volumetric images. CT scanning, however, has limited soft-tissue contrast resolution compared with MRI scanning. This is particularly relevant to evaluating upper airway adipose tissue. Other limitations of CT scanning include

60 Review of Literature expense and the radiation exposure patients receive each time they are studied. Nonetheless, upper airway imaging studies with CT scanning has enhanced our understanding of upper airway anatomy and its relationship to OSA (Aksoz et al., 2004 and Akan et al., 2004). Most of the studies using CT have evaluated airway dimension during states of wakefulness and sleep and have shown narrowing predominantly in the retropalatal region in patients with OSA (Shepard et al., 1989 and Burger et al., 1992). In addition, the degree of narrowing has been correlated directly with OSA severity. Volumetric CT studies have demonstrated smaller airway caliber and larger tongue volume in obese patients with OSA (Fleetham, 1992). Three-dimensional CT has shown that the most important parameter associated with sleep-disordered breathing appears to be narrowing at the retropalatal area and that lateral airway caliber compromise correlates with the apnea- hypopnea index (AHI). CT studies have also been employed to try to identify favorable surgical candidates for uvulopalatopharyngoplasty (UPPP) and to examine dynamic changes of the upper airway and surrounding soft tissue structures during respiration (Davies et al., 1992 and Strobel et al., 1996). These dynamic CT imaging studies have shown that the upper airway is narrowest at end-expiration and early-inspiration in both normal and apneic subjects (Strobel et al., 1996 and Li et al., 2003). Cephalometry: Lateral cephalometry is a simple and well-standardized technique involving radiographs of the head and neck with focus on bony and soft tissue structures. Several cephalometric studies

61 Review of Literature have been performed in OSA patients and have provided important insights (Pae et al., 1994 and Mayer et al., 1996). Most of these studies have investigated the airway with the subject in the upright position, although comparisons between upright and supine postures have been made. An upright lateral cephalograph is obtained while the subject is seated with gaze parallel to the floor and teeth together (Pae et al., 1997 and Ingman et al., 2004) Investigators have used radiopaque material to enhance the outline of the oropharyngeal structures. The cephalometric images are used to study measurements of many set points, planes or distances within the head and neck region. The cephalometric technique has highlighted important differences between sleep apneics and normal subjects, sleep apneics and snorers, and obese and nonobese subjects (Fergusonet al., 1995). OSA patients have been shown to have a small posteriorly-placed mandible, a narrow posterior airway space, an enlarged tongue and soft palate, and an inferiorly located hyoid (deberry-borowiecki, 1988 and Shepard et al., 1991). All five of the above variables have been shown to be significant determinants of apnea severity. The craniofacial abnormalities in OSA patients are reported more frequently in the subgroup of patients who are not obese. OSA patients compared with snorers have been demonstrated to have a longer soft palate in addition to an inferiorly positioned hyoid bone and posteriorly displaced mandible. Interestingly, when subdivided for age or body mass index (BMI), it was found that the significant differences between upper airway dimensions of OSA patients and snorers in the overall population were almost exclusively derived from the younger (age < 52 years) and leaner (BMI <

62 Review of Literature 27 kg/m2) subgroups. The upper airway measurements studied in obese or older OSA patients were not different from obese or older snorers (Mayer et al., 1996 and Nelson et al., 1997). More recent work with supine cephalometry has shown that the transition from upright to supine position in sleep apneics is associated with a significant narrowing of the oropharyngeal sagittal dimension Cephalometry has also been employed to assess and optimize the efficacy of mandibular advancement oral appliances based on the anatomical changes in supine imaging (Tsuiki et al., 2004). Limitations of cephalometry pertain to the two-dimensional nature of the image and to the examination of soft tissue. Cephalometry provides two-dimensional static images in the sagittal plane and therefore cannot provide information about transverse dimensions, cross-sectional shape or volume, or dynamic changes of the airway during sleep. The patient is required to be awake and therefore extrapolation to the sleep state may be inaccurate (Ingman et al., 2004). Using the above mentioned methods there are three basic types of airway obstruction (Ingman et al., 2004). Type I: Obstruction of the upper part of the throat. Many patients will have: Long and thickened soft palate Narrow width and depth of the upper throat Large uvula with wrinkling or "telescoping" of excess tissue Mucosal webs Bulge from hypertrophy of muscle in the throat Redundant mucosal folds

63 Review of Literature Type II: Combined upper and lower obstruction of the throat Collapsing and obstruction from the sides of the throat Obstruction involve both palate and tongue base segments Type III: Obstruction of the lower part of the throat Obstruction at the base of the tongue Increased lingual tonsils (base of the tongue) Large tongue Redundant tissues of the upper voicebox Although the prevalence of obstructive sleep apnea (OSA) and its health consequences are still under study, it is apparent that significant morbidity and mortality are associated with OSA, even for those younger than 50 years of age. Preliminary evidence suggests that patients with OSA have an in creased susceptibility to cardiovascular complications such as hypertension, cardiac arrhythmias, stroke and myocardial infarction. A possible common mechanism for these adverse outcomes is increased sympathetic nervous system activity, known to be present in patients with OSA (Lugaresi, 1980; Guilleminault et al., 1983 and Bliwise, 1988). Most likely, hypoxemia present in sleep in patients with OSA contributes to this increased sympathetic nervous system stimulation and to its adverse consequences. Whether OSA is an independent risk factor for cardiovascular disease separate from obesity,hypertension, and diabetes is currently under investigation by a National Institutes of Health-sponsored, multicenter, prospective study. Excessive daytime sleepiness also is a major complication of OSA. Impairment of alertness may make one susceptible to work or driving accidents and/or to poor work and social functioning. Thus, the rationale for treatment of OSA is based on the following:

64 Review of Literature (1) Susceptibility of patients with OSA to major cardiovascular illness and hypoxic complications, and (2) the consequences of excessive daytime sleepiness (Carlson, 1993). The options of treatment of OSAS are as follows: weight loss, nasal-continuous positive airway pressure, (N-CPAP), pharyngeal surgery, and pharmacologic treatment. Weight Loss: Obesity has been known to be a common clinical characteristic of patients with OSA for some time. Both anatomic and physiologic abnormalities may exist because of obesity in patients with OSA. More recent investigations demonstrate that body fat tends to be distributed in the upper body in patients with OSA, such that neck obesity and pharyngeal fat deposition may be important (Suratt et al., 1987; Horner et al., 1989 and Shelton et al., 1993). Shelton et al (1993) found a correlation between the severity of OSA and the volume of pharyngeal adipose tissue, as detected by MRI. In two patients studied after weight loss and improvement in the OSA, these investigators found that the volume of pharyngeal fat had decreased. Weight loss also has been associated with an improvement in upper airway function found less pharyngeal collapsibility in patients with OSA after weight loss; and found an increase in the pharyngeal airway crosssectional area, as measured by acoustic reflection, in OSA patients following weight loss. Weight loss is quite effective in decreasing the number of apneic events, the extent of arterial oxygen desaturation, and

65 Review of Literature the amount of sleep disruption seen in patients with OSA (Loube et al., 1994). Weight reduction surgery has been used in obese OSA patients (Charuzi et al., 1985). In a very interesting series, Sugerman et al (1992) showed that gastric reduction or bypass surgery was quite effective in treating obese individuals with sleep-related alveolar hypoventilation (pickwickian syndrome), those with OSA, or patients with a combination of both. Patients who had a polysomnogram following surgery had a mean weight loss of 57 kg, a decrease of 32% from their initial weight. Nasal-Continuous Positive Airway Pressure: By producing a positive pressure within the upper airway to counteract the subatmospheric collapsing pharyngeal pressure produced during an obstructive apnea, N-CPAP is an effective treatment for OSA. However, the success of N-CPAP is hampered by poor compliance by many OSA patients. It is not hard to understand why wearing a cumbersome facemask throughout sleep every night would be difficult. However, since nearly all patients can tolerate N-CPAP beyond the sleep laboratory (85 to 92% of patients28), and since nearly all notice a beneficial effect of this device, poor compliance becomes somewhat more difficult to understand (Hoffstein et al, 1992). In addition to the noise and cumbersome nature of the N-CPAP compressors (variables on which industry continues to improve), a high percentage of OSA patients complain of nasal or oral dryness, nasal congestion, sneezing, sinusitis, nose bleeds, and/or rhinorrhea. Skin reactions from the facemask, nasal bridge abrasions, red eyes, and aerophagia are commonly reported. In these studies, nasal dryness

66 Review of Literature was observed more frequently in those with more serious OSA, but the severity of the OSA was not a factor in the presence of other side effects. Humidification of the N-CPAP system or the level of N-CPAP required did not influence the presence of these symptoms (Pepin et al., 1995). The success of N-CPAP treatment is directly dependent on the patient's willingness to wear the device. Earlier studies of N-CPAP compliance, based on patient report, demonstrated very good compliance (Sanders et al., 1986 and Rolfe et al., 1991). Interestingly, compliance was no better with bilevel pressure application than with continuous pressure. Examination of factors that might predict N-CPAP compliance has been conducted. Severity of disease and the level of N-CPAP required to control the OSA were not always helpful; the level of education and the degree of improvement sensed by the patient after N-CPAP use appeared to be variables that may be predictive of long-term good N-CPAP compliance Thus, bettereducated individuals with more severe disease likely will use their NCPAP more regularly than those with a low level of education and/or less severe disease. Other forms of treatment may be more appropriate for the latter group of patients (Kribbs et al., 1993 and Meurice et al., 1994). Surgery of OSAS: Several operative procedures have been developed for the treatment of OSA. Although it would be ideal to recommend the procedure of choice to a given patient based on a characterization of the upper airway anatomy and/or physiology, site of upper

67 Review of Literature airway obstruction, prediction of surgical success by site of obstruction identification, and operative procedures available. Type of Surgical Procedures Used: The original surgery performed for OSA was the tracheostomy. Although tracheostomy is effective in decreasing the mortality and morbidity of OSA, tracheostomies are often complicated by local infection and/or bleeding around the tracheostomy stoma. Aesthetically, tracheostomies are less than optimal from the patient's perspective (Partinen et al., 1988 and Partinen et al., 1990). The most widely used technique is the UPPP. In general, this procedure is effective in one half of the patients (Fujita et al., 1981 and Conway et al., 1985).figure(13,14 )

68 Review of Literature Figure (13):(A) showing uvula and pillar before operation, (B)early post operative (c) late post operative Notice resected uvula. Grontved and Karup (2000) Figure( 14 ):early post uppp showing sutures. Grontved and Karup (2000)

69 Review of Literature Interestingly, UPPP seems to improve symptoms of OSA, even though minimal improvement is observed in the apnea pattern. The etiology of this seemingly paradoxical situation is unclear. UPPP does have an effect on upper airway physiology in that it decreases the collapsibility of the upper airway, although the success of surgeiy was not found to be predictable from the preoperative measurement of upper airway collapsibility (Schwartz et al., 1992 and Miljeteig et al., 1994). Launois et al, (1993) reported that the beneficial effect of UPPP may not be long lasting. Most of those failures over this time interval were in patients who had gained significant weight. These data indicate the need to do postoperative polysomnograms to detect initial nonresponders and to monitor patients long term to help them lose, or at least not gain weight. If weight gain occurs post-uppp, a polysomnogram may be advisable to detect worsening. If the apnea has reappeared or is worse, then CPAP may be needed. Of course, if weight gain has occurred, then dietary counseling should be reinstituted. Other operative procedures have been used to treat OSA. To increase the caliber of the hypopharyngeal airway, the hyoid suspension and genioglossus advancement procedures were developed (Riley et al., 1989). It is difficult to examine the response to individual operative interventions, since they are often done in combination with other procedures. Johnson and Chinn (1994) reported a reduction of the AHI of at least 50% in six of nine patients studied with genioglossus advancement in addition to UPPP. Another operative procedure that increases the hypopharyngeal cross-sectional area is mandibular advancement, done with or without maxillary advancement. Success has been variable, but generally better than that experienced with UPPP.

70 Review of Literature Twenty of 21 patients with mandibular-maxillarydeficiency and OSA had improved conditions with an average mandibular/maxillary advancement of 10 mm." In a study of patients referred for mandibular advancement for retrognathia, not OSA, Yu et al (1994) found no relationship between the amount of mandibular, and/or mandibular/maxillary advancement, and change in the cross sectional hypopharyngeal area, as measured by lateral cephalometric examination. Most interesting, these investigators found that the postoperative hypopharyngeal airway cross-sectional areas decreased over a mean follow-up period of 15 months. If there is a return toward the original airway size over time, then the long-term results with this procedure for OSA also may not be favorable, similar to new findings with UPPP. Midline glossectomy has been proposed as simpler treatment of hypopharyngeal obstruction (Fujita et al. 1991) Used in those who had not responded to UPPP, as, well in those patients who had not had a UPPP, but who demonstrated narrowing of the airway at the base of the tongue, midline glossectomy decreased the AHI to fewer than 20 events per hour of sleep in 17 of 22 OSA patients (Woodson et al., 1992). Riley et al (1993) have taken a progressive approach to the surgical treatment of OSA. Surgery was planned for those who could not accept or tolerate N-CPAP. A preoperative examination of the upper airway was done with cephalometrics and the Muller maneuver. The operative approach depended on the identification of the site of obstruction or upper airway narrowing during these studies. Stage 1 surgery was the following: for those with retropalatal obstruction alone, a UPPP was performed; for patients with hypopharyngeal obstruction alone, genioglossus advancement and hyoid suspension were performed without

71 Review of Literature UPPP; and for patients with obstruction at both sites, all three procedures were performed. For those who failed stage 1 surgery, stage 2 surgery was offered. This consisted of mandibular advancement. Laser-assisted uvulopalatoplasty has been developed to treat snoring and OSA on an outpatient basis. However, little objective data are available to assess this procedure's efficacy. One drawback is that the conditions of some patients worsened with this procedure (Kamami et al., 1994). Recent reports demonstrating a good response to dental appliances have appeared. These devices advance the mandible nonsurgically. Snoring, apnea counts, oxygenation, and sleep quality all improve with the dental appliance. Good compliance is reported, but of course, cannot be objectively assessed (Clark et al., 1993). Radiofrequency surgery is a minimally invasive technique used to reduce the bulk of the tongue at its base. The beneficial effects of radiofrequency surgery are likely a result of changes in upper airway collapsibility and not alteration of the upper airway anatomy. Tonguebase suspension procedures, in combination with UPPP, have been shown to be more efficacious than UPPP alone (Bäck et al.,2009). Palatal implants have recently attracted attention as a potential treatment for mild-to-moderate OSA. This is a minimally invasive approach in which 3 implants are placed inside the soft palate centered around the uvula. The morbidity is minimal because this approach can be performed in a clinic and no mucosa is cut. If successful, the patient avoids both the operating table and the chronic use of the CPAP machine. The palatal implant method has the potential to significantly

72 Review of Literature improve AHI in patients with mild-to-moderate OSA, minimal tonsillar hypertrophy, uvula elongation, and a BMI of less than 30. Short-term results are comparable with those reported for UPPP without the associated morbidity. In a recent study by Friedman, palatal implants were found to be a valuable mode of treatment for patients whose symptoms failed to improve after surgery, namely UPPP.The subjective improvement of symptoms was significant (WALKER etal.,2007). Oro pharyngeal muscles exercise: Oropharyngeal exercises derived from speech therapy may be an effective treatment option for patients with moderate OSAS. Thirty one moderate OSAS patients were randomized to 3 months of daily (~ 30 min) of oropharyngeal exercises,consisting of exercises involving the tongue, soft palate, and lateral pharyngeal wall. Anthropometric measurements, snoring frequency intensity, Epworth daytime sleepiness, Pittsburgh sleep quality (0-21) questionnaires and full polysomnography were performed at baseline and at study conclusion. Body mass index and abdominal circumference did not change significantly over the study period. No significant change occurred in the control group in all variables. In contrast, patients randomized to oropharyngeal exercises had a significant decrease (P<0.05) in all this parameters Changes in neck circumference correlated inversely with changes in AHI (Katia etal, 2009). Pharmacologic Treatment of OSA: Various pharmacologic agents have been used to treat OSA. None used to date has been completely successful, but some compounds are as effective as surgery, or may be as effective as N-CPAP. If a truly effective and safe pharmacologic agent could

73 Review of Literature be identified, such a treatment would be a convenient alternative to surgery or N-CPAP. Although, at this time such a pharmacologic panacea does not exist, there are some medications that show promise in treating at least a portion of OSA patients (Nicholas, et al; 2007). There are several mechanisms by which pharmacologic agents might improve OSA, ranging from effects on sleep character to effects on neural control of breathing. For instance, some pharmacologic agents may alter sleep stage distribution and thereby decrease the time of the stage of sleep where the apneas predominate. Antidepressant agents decrease or nearly eliminate rapid eye movement (REM) sleep. If a given patient has most apneas in REM sleep, then a trial of a nonsedating antidepressant to diminish REM sleep time maybe helpful (Driver et al., 1995). In contrast, if low ventilatory drive activity is present, as indicated by alveolar hypoventilation awake, for instance as often occurs in hypothyroidism, then agents that stimulate ventilatory drive, such as thyroxine or medroxyprogesterone may improve the OSA in such a patient. Since OSA is more prominent in postmenopausal women, progesterone treatment may be especially helpful to the postmenopausal woman with OSA. Agents that eliminate periodic breathing in sleep, such as acetazolamide, may eliminate OSA in patients with an underlying dysrhythmia of ventilation. Pharmacologic agents that help obese OSA patients lose weight should be helpful in the management of the OSA. Decongestant medications may decrease not only nasal congestion that may play a role in snoring in those with allergic or non allergic rhinitis, but they may also decrease pharyngeal edema that is present in patients with OSA (Kuriyama, 1990).

74 Patients & Methods Patients and Method This study was conducted on fifty seven subjects who admitted to the sleep disordered- breathing unit(sdbu) in chest department of Mansoura University hospital during the period from April 2005 to February These subjects were divided into two groups: OSAS group included forty seven newely diagnosed patients were selected randamally from patients admitted to SDBU in our chest department because of excessive day time sleepiness or snoring. This group included 22 male (mean age, years; range, years) and 25 female (mean age, 47.6 years; range, years). The other group was ten subjects as a control group matched to patients with OSAS by age and sex. Control subjects were selected from workers of the hospital and relative of patients after verbal consent. Exclusion criteria included: (1) Chronic respiratory disease such as asthma, COPD or IPF (2) Diabetic patients (3) System failure: cardiac, hepatic or renal (4) Evidence of a neurological disorders (5) Hormonal disorders Methods All patients were subjected to the following A- Clinical assessment including

75 Patients & Methods 1- A thorough history taking including age, gender, smoking habits, respiratory symptoms such as (cough, expectorations, dyspnea and wheeze) 2- History of habitual snoring, restless sleep, rest leg syndrome (Stehlik R, Arvidsson L, Ulfberg J, 2009), sleep wake, sleep take morning headaches, daytime hypersomnolence (Murray Johns 1997), intellectual deterioration and insomnia (Passarella S, Duong 3- Epworth Sleepiness Scale (ESS) (Murray Johns, ): was used to measure daytime sleepiness 4- Berlin Questionnaire (for sleep apnea) (Netzer, et al., 1999): for detection of patients risky for OSAS B-physical examination 1- ENT examination including Examinations of nasal mucosa: congested, pale, dull red or pale purple, presence or absence of nasal discharge (clear mucoid, copious watery or colored discharge) presence or absence of ethmoidal polyps, septal deviations, septal spur, hypertrophied turbinate. Examinations of oro-pharynx (overcrowded mouth, increase size of the tongue (markes of teeth on sides), long uvula and high arched palate.

76 Patients & Methods Figure (15) show case 4: Enlarged uvula resting on the base of the tongue (large arrow), along with hypertrophied tonsils (small arrows). The posterior pharyngeal erythema may be secondary to repeated trauma from snoring or gastroesophageal reflux Friedman classification The Friedman classification was developed to predict the successful outcome of surgery, specifically UPPP, for OSA patients. It is a modified version of the Mallampatti classification that is used to evaluate palate position relative to oropharyngeal size. In Friedman's classification, the patient keeps his tongue in a neutral position and 4 stages are used to describe the airway (Friedman, 2006). It includes an evaluation of palate position, tonsil size, and body mass index (BMI). The palate position is graded from I-IV, as follows: I: The uvula, soft palate, and tonsils/pillars are clearly visible. II: The uvula and soft palate are visible, but the tonsils are not. III: Only part of the soft palate is visible. IV: Only the hard palate is visible.

77 Patients & Methods The tonsil size is graded from 0-4, as follows: 0+: A previous tonsillectomy has been performed. 1+: The tonsils are hidden within the tonsillar pillars. 2+: The tonsils extend to the tonsillar pillars. 3+: The tonsils extend beyond the pillars but not to the midline. 4+: The tonsils extend to the midline. Friedman classification: Body mass index is determined to be less than 40 kg/m2 or more. Stage I and Stage II only are subjected to the surgery in our study. Table (3): Staging system of Friedman Stage I Stage II Stage III Friedman Tonsil Body Mass Index Palate Position Size (kg/m2) 1 3, 4 < , 4 < 40 1,2 0, 1, 2 < 40 3,4 3, 4 < , 1, 2 Any 4 0, 1, 2 Any Any Any > General examinations Anthropometric measurement: They included measurement of body weight (kg.), body height (cm.) neck circumference and MAC Body mass index (BMI): Body mass index (BMI) is obtained by dividing weight (kg) by the square of the height (m2): BMI = W/H2

78 Patients & Methods Table (4) provides classification of Obesity according to National Institute of Diabetes and Digestive and Kidney Diseases, 1988) BMI 18.5 or less Underweight Normal Overweight Obese I ObeseII 40 or greater Extremely Obese Neck circumference (NC): The neck circumference (cm) was measured with the subject in the standing position at the level of the cricothyroid cartilage. with plastic tape. In men with a laryngeal prominence (Adam's apple), it was measured just below the prominence. All circumferences were taken with the subjects standing upright (World Health Organization, 2000). Mid-arm circumference (MAC): Measurement of mid- arm circumfrenc of the non dominant arm was taken midway between the acromion and the olacranon process by means of a tape. Normally it is ranged from cm (Alpers et al, 1998). Flexible nasopharyngoscopy All subjects were subjected to Flexible nasopharyngoscopy. It allows examination of the nose, all portions of the pharynx, and the larynx all in one procedure. When performing the nasopharyngoscope dynamic tests are possible. Beginning in the rhinopharynx. The patient is asked to perform Müller maneuver. This maneuver is useful to assess the

79 Patients & Methods collapsibility of the pharynx. The base of the tongue and the glossoepiglottic recesses are examined by asking the patient to extend his/her tongue. Evaluating the diameter of the pharynx and the characteristics of the epiglottis is also possible. The Müller maneuver is performed with the nasopharyngoscope in the pharynx. The patient is asked to breathe while the lips are closed and the physician closes the nasal valves with his/her fingers. In this way a negative pressure is created in the pharyngeal area and evaluating the retropalatal, retroglossal, and retroepiglottic spaces is possible (Morrell et al., 1998). Plain X-ray chest to exclude pulmonary, cardiac, and chest cage abnormality. Pulmonary function tests: We stress on FEV1, FVC,FEV1 / FVC ratio and RV and TLC Arterial blood gases analysis: Arterial blood sample was taken to check gas tension and acid base status at the morning follow sleep study, using blood gas analyzer with special attention to arterial oxygen tension (PaO2) Arterial carbon dioxide tension (PaCO2) and arterial ph Verbal consent was taken for all cases for non invasive maneuvers and written consent taken for surgical operation with ENT surgen After careful physical examinations, all of the patients spent one or two nights in the sleep disorders laboratory unit.

80 Patients & Methods Diagnosis of OSAS was confirmed by analysis of the entire PSG record on the day following sleep studies. Sleep studies: All patients underwent full-night Polysomnography (PSG) studies with 16 channels with standardized polysomnographic techniques that included monitoring of the electroencephalogram (EEG) (C3-A2), electrooculography (EOG), submental electromyography (EMG), electrocardiography (ECG), flow (thermistor), respiratory and abdominal effort (thoracic and abdominal belt), leg movements. body position. In addition, quantitative snoring intensity with a microphone was placed over the patient s trachea (fig.13). and arterial oxygen saturation levels were continuously recorded with an oxygen saturation sensor was placed on the fifth finger of each subject, and Data were recorded on computer. Bedtime was between 22:00-23:00 and 06:00 (all patients were awakened at 06:00). Figure (16): show full polysomnography

81 Patients & Methods Figure (17): show patient connected to polysmnography.

82 Patients & Methods Figure (18): show epoch with obstructive sleep apnea notice arawsa and decrease desaturation at the end of the apnea.

83 Patients & Methods Scoring and definitions All scoring was performed based on standard criteria. Apnea was defined as the complete cessation of air- flow for at least 10 sec. Hypopnoea was defined as decrement in flow by 30%, if it was associated with oxygen desaturation (of 4% or more). The minimal oxygen saturation was determined as the lowest saturation value that was associated with a respiratory event. Also snoring index was calculated. Apnea hypopnea index was calculated by dividing the total number of apneas + hypopnoeas by total sleep time. The patients examined in this study were selected more than 10 AHI with symptoms. Sleep stages were determined by the criteria of Rechtschaffen and Kales (1968). Cephalometry Lateral cephalometric radiographs (Riley et al, 1993 technique). The patient is seated with the head in a neutral position, the gaze parallel to the floor, and the teeth together. The X-ray plate is placed next to the left side of the face, and the collimator was placed 1.5 m from the patient. Exposures are performed while the patient remained still and slowly exhaled. Ear rods were inserted into the external auditory meati to stabilize the head posture during exposure. The patients were instructed not to swallow during the cephalometric procedure. Cephalometric evaluations of the patients was done on lateral cephalograms. Cervico-craniofacial skeletal reference points and lines

84 Patients & Methods were used for linear and angular measurements. The posterior airway space, localization of the hyoid bone and maxillary and mandibular developmental status were carefully evaluated SNA angle measures the projection, anterior or posterior, of the maxilla. The reference range value is 82 ± 2. SNB angle measures the position of the mandible. The reference range value is 80 ± 2. Less than this is considered retrognathia. ANB angle measures the position of the maxilla with the mandible. The reference range value is 2. This measures prognathism. PAS or retroglossal space; the reference range is mm MP-H is the distance between the mandibular plane (MP) and the hyoid bone (H). The reference range is mm. The longer the distance, the higher the possibility of the patient having OSA (fig. 19).

85 Patients & Methods Figure (19): Lateral cephalometric radiograph showing the Cervico-craniofacial skeletal reference points and lines used for linear and angular measurements.( A: subspinale =the most posterior midline point in the concavity between the anterior nasal spine and the lowest point on the alveolar bone overlying the maxillary incisors,b: Supramentale = the most posterior medline point on the anterior concavity of the mandibular symphysis SNA: Maxilla protrusion angle, SNB :mandibular protrusion angle ANB:maxilomandibular discrepancy, ANS-PNS: sagital length of maxilla GN-GO :length of the body of the mandibule,mp-h: mandibular plane hyoid distance,pas: posterior airway space retroglossal). Magnetic Resonance Imaging Image Processing and Anatomic Measurements

86 Patients & Methods MR images were made in the radiology department, Mansoura university hospital. Airway measurements of soft tissue and bony structure segmentation were performed by manual tracing. Axial and sagital sequential T1-weighted (TR [repetition time], 650 ms; TE [echo time], 14 ms) and T2-weighted (TR, 6,000 ms; TE, 90 ms) images with 3-mm slice thickness were obtained from the orbital cavity to the larynx and from the midline bilaterally, respectively. Two measurements (maximum and minimum) to be obtained for the surface area and diameters of the airway. These changes in images will be parallel to the respiratory motion. Subjects were positioned supine with the head in a neutral anatomical position secured with tape Patients are instructed to refrain from swallowing during scanning and to breathe through their nose with the mouth closed. The patient's head is positioned supine in the soft tissue Frankfort plane (tragus of the ear to orbital fissure) perpendicular to the table. A median sagittal image in which the lingual septum and the odontoid process of the second cervical vertebra were distinguished was employed for sagittal measurements. Sagittal Measurements Nasopharyngeal airway was defined radiologically as being bounded anteriorly by the vomer, posteriorly by the adenoid, and inferiorly by a horizontal line above the hard and soft palate The diameter of the nasopharynx was measured at the narrowest point between the adenoid tonsils (or the posterior pharyngeal soft tissues

87 Patients & Methods in patients without recurrent adenoid tonsils after adenoidectomy) posteriorly and the posterior aspect of the soft palate anteriorly. Nasopharnyx Retropalatal narrowing Figure (20): From a midsagittal T1-weighted image show the nasopharynx and retroplatale narrowing

88 Patients & Methods Surface area of the tongue Figure (21): show surface area of the tounge Surface area of the softpalate and Retroplatal obstruction Figure (22): show surface area of the soft palate and retroplatal obstruction

89 Patients & Methods The following sagittal measurements were obtained (Ciscar etal.,2001) : 1. The anteroposterior length of the tongue (AP tongue): defined as the distance between the tip of the tongue and its posterior border) N.= CM) 2. The craniocaudal length of the soft palate (CCsoftpal): defined as the distance between the posterior nasal spine and the tip of the uvula N= (2-4.3CM) (fig.23). 3. The anteroposterior dimension of the soft palate (APsoftpal): defined as the anteroposterior measurement of the soft palate in its thicker region (N= cm). Cc lenght of soft palate Figure (23): Midsagittal T1-weighted MRI showing the craniocaudal length (CC length) of soft palate Axial Measurements

90 Patients & Methods The morphology of the pharyngeal air column was also observed. Linear laterolateral (LL) and anteroposterior (AP) axial measurements were obtained at the following levels (Ciscar etal.,2001) Rhinopharynx: axial pharyngeal image at the hard palate level (1.52.7cm, cm). At oropharynx: oropharyngeal airway was defined radiologically as being bounded anteriorly by the soft palate or tongue, laterally by the tonsils, and posteriorly by pharyngeal constrictor muscle. It is dived into: Retropalatal oropharynx (Level 3): pharyngeal measurements at the uvula level or at the narrowest air column point of the low retropalatal region ( cm, cm). Retrolingual oropharynx (Level 4): measurements obtained in an intermediate image between the uvula and the tip of the epiglottis (1.54cm, cm) Nasopharnyx Fig (24): show nasopharynx

91 Patients & Methods uvula and retroplatale oropharynx Figure (25): show the retroplatal oropharynx

92 Patients & Methods Figure (26): Show retroglossal oropharynx

93 Patients & Methods Figure (27): airway lateral diminution than AP of one of the control subject,notice increase

94 Patients & Methods