Sleep-Disordered Breathinglsneuro.org/files/c/mouvementdisorders/Sleep-Disorders... ·...

Sleep-DisorderedBreathing

Lori Panossian, MD, MS; Joseph Daley, MD, PhD

ABSTRACTPurpose of Review: This article introduces readers to the clinical presentation,diagnosis, and treatment of sleep-disordered breathing and reviews the associatedrisk factors and health consequences.Recent Findings: Sleep-disordered breathing is associated with significant impair-ments in daytime alertness and cognitive function as well as adverse health out-comes. The initial treatment of choice is positive airway pressure. Improvements intechnology and mask delivery systems have helped to make this treatment morecomfortable and convenient for many patients.Summary: Sleep-disordered breathing, particularly in the form of obstructive sleepapnea, is highly prevalent in the general population and has important implicationsfor neurology patients. Sleep-disordered breathing is characterized by repetitive pe-riods of cessation in breathing, termed apneas, or reductions in the amplitude of abreath, known as hypopneas, that occur during sleep. These events are frequentlyassociated with fragmentation of sleep, declines in oxygen saturation, and sym-pathetic nervous system activation with heart rate and blood pressure elevation.Obstructive sleep apnea, which represents cessation of airflow, develops because offactors such as anatomic obstruction of the upper airway related to obesity, excesstissue bulk in the pharynx, and changes in muscle tone and nerve activity duringsleep. Central sleep apnea represents cessation of airflow along with absence orsignificant reduction in respiratory effort during sleep and is more commonly foundin the setting of congestive heart failure, neurologic disorders, or cardiopulmonarydisease.

Continuum (Minneap Minn) 2013;19(1):86–103.

INTRODUCTIONSleep-disordered breathing is an over-arching term used to describe variousdistinct or occasionally overlapping syn-dromes, including obstructive sleepapnea (OSA), central sleep apnea,and hypoventilation. Sleep-disorderedbreathing is characterized by intermit-tent periods of apnea, hypopnea, orrespiratory effortYrelated arousals(RERAs). Obstructive apnea events con-sist of transient cessations in airflow(90% or greater airflow reduction forat least 10 seconds, as defined by theAmerican Academy of Sleep Medicine[AASM]), whereas hypopneas are char-

acterized by diminished amplitude ofthe inspiratory breath (30% to 90% air-flow reduction for at least 10 secondswith at least 4% reduction in baselineoxygen saturation), as depicted inFigure 5-1.1 Although the AASM rec-ommends the former definition of ahypopnea, the alternative AASM defi-nition may be appropriate to use forselected patients: a hypopnea is scoredwhen airflow drops by at least 50% forat least 10 seconds with either anassociated 3% or greater reduction inoxygen saturation, or an associatedarousal from sleep.1 RERAs are periodsof increased respiratory effort with

Address correspondence toDr Lori Panossian,University of Pennsylvania,Translational ResearchLaboratories, 125 South31st St Room 2125,Philadelphia, PA 19104,[email protected].

Relationship Disclosure:Drs Panossian and Daleyreport no disclosures.

Unlabeled Use of

Products/InvestigationalUse Disclosure: Drs Panossianand Daley report nodisclosures.

* 2013, American Academyof Neurology.

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decreased airflow, crescendo snoring,and transient EEG arousals from sleepthat do not meet AASM criteria forapneas or hypopneas.2

The respiratory events that occur insleep-disordered breathing are typicallytransitory and self-limited. They ofteninduce brief arousals or microarousalsfrom sleep, which in turn restore anormal breathing pattern.3 Apneas andhypopneas frequently cause transientoxygen desaturation, but this may notalways occur, especially among patientswith normal baseline pulmonary func-

tion. A subtype of sleep-disorderedbreathing termed upper airway resist-ance syndrome occurs among somepatients with primarily RERAs, withoutassociated significant oxygen desatura-tion or frank apneas and hypopneas.Upper airway resistance syndrome isthought to have similar pathophysiol-ogy and presents with similar symp-toms as OSA.2

OSA occurs as a result of apneas andhypopneas that are primarily caused byphysical obstruction of the extrathoracicupper airway. Typically during these

KEY POINTS

h An obstructive apnea isdefined as cessation ofairflow with continuedrespiratory effort due tocomplete upper airwayocclusion.

h A hypopnea is a partialdecrement in airflow withan associated physiologicconsequence, either anarousal or oxygendesaturation, due topartial upper airwaycollapse.

FIGURE 5-1 Polysomnographic example of obstructive apnea. A 60-second epoch of polysomnography during non-REM stageN2 sleep demonstrating an obstructive apnea, defined as a 90% or greater loss of airflow for at least 10 secondswith preserved respiratory effort. Note the absence of airflow through the nose and mouth despite ongoing

respiratory effort (as seen by the tracings of thoracic and abdominal movement), signifying obstruction of the upper airway withconsequences including oxygen desaturation and an EEG arousal from sleep. Channels from top to bottom represent EEG (left andright central, left and right occipital), electrooculogram (left and right eyes), chin EMG, EKG, snoring, nasal pressure transducer, oralthermistor, respiratory effort (thoracic and abdominal movement), and arterial oxygen saturation.

EEG = electroencephalograph; EMG = electromyogram; EKG = electrocardiogram; SaO2 = arterial oxygen saturation.

87Continuum (Minneap Minn) 2013;19(1):86–103 www.aan.com/continuum


events, complete or partial collapse ofsoft tissue and pharyngeal musculatureoccurs during sleep. This pattern canvary by stage of sleep and by body orhead position and tends to be partic-ularly severe when in the supine posi-tion or during REM sleep. The normalskeletal muscle atonia associated withREM sleep can exacerbate airway col-lapse in susceptible people.4,5

On the other hand, central sleepapnea (CSA) is unrelated to physicalobstruction but instead is caused by

cessation or significant reduction inrespiratory effort or drive (Figure 5-2).Respiratory effort, mediated by CNSbrainstem respiratory control centersin the pons and medulla, can beassessed during polysomnography(PSG) by the use of thoracic andabdominal respiratory inductance ple-thysmography belts. The belts detectmovements of the chest and abdomenduring inspiration and expiration,which are surrogates for respiratoryeffort. In central apnea, transient

FIGURE 5-2 Polysomnographic example of central apnea. A 60-second epoch of polysomnography during non-REM stage N1sleep demonstrating a central apnea, defined as a minimum of 10 seconds of airflow loss with associated absenceof respiratory effort. Note the absence of airflow through the nose and mouth and the loss of respiratory effort in

the chest and abdomen. The event is terminated by an EEG arousal from sleep. Channels from top to bottom represent EEG (leftand right central, left and right occipital), electrooculogram (left and right eyes), chin EMG, EKG, snoring, nasal pressure transducer,oral thermistor, respiratory effort (thoracic and abdominal movement), and arterial oxygen saturation.



Sleep-Disordered Breathing


pauses in respiratory effort result incessation of airflow, often followed byoxygen desaturation or an arousal fromsleep. Combinations of central and ob-structive apneas can occur in the sameindividual, a condition termed complexsleep apnea syndrome when theevents occur with sufficient frequency.When a combination of central andobstructive components occurs withinthe same breath, it is termed a mixedapnea. During mixed apneas, no res-piratory effort occurs during the initialportion of the breath, followed byresumption of effort but persistentlydiminished or absent airflow.

OBSTRUCTIVE SLEEP APNEAEpidemiology and Risk FactorsOSA is highly prevalent in the generalpopulation. Population-based studiesestimate the prevalence of OSA amongworking people aged 30 to 60 to beapproximately 2% of women and 4% of

men.6,7 When not including sleepinesssymptoms in the criteria, the preva-lence of OSA characterized solely byapnea or hypopnea events is 9% amongmiddle-aged women and 24% in men.This number may actually be an under-estimate of the true prevalence. Mostepidemiologic studies for OSA wereperformed during the previous 2 de-cades; in the interim, advances haveoccurred in the sensitivity of polysom-nographic equipment (thereby increas-ing the likelihood of detection of OSA),and rates of obesity, which is a majorrisk factor for OSA, have significantlyincreased.8 OSA is 1.5 to 4.0 timesmore common in men, and prevalencealso increases with age.7,9 After meno-pause, women’s risk approximates thatof men (Case 5-1).7 Craniofacial bonydimensions are a significant contributoreven in the absence of obesity, espe-cially among Asian populations andsome whites.10

KEY POINTS

h A mixed apnea isdefined as a period ofairflow cessation withoutrespiratory effort followedby a period of resumedeffort with continueddecrements in airflow.

h Obstructive sleep apneais a highly prevalentcondition that occurspredominantly inmiddle-aged orolder men andpostmenopausal women.

Case 5-1A 63-year-old woman reported unrefreshing sleep and frequent awakenings during which she feltsweaty and hot with nocturia twice nightly. She snored softly and often awoke with a dull bitemporalheadache that resolved spontaneously within hours. She was postmenopausal, and her daytime hotflashes had stopped at age 56. She requested a prescription for sleeping pills to prevent awakenings.

During the day, she felt tired and had difficulty concentrating and remembering tasks. She slept for8 hours nightly and had a regular bedtime. She had no cataplexy, sleep paralysis, hypnagogichallucinations, or dream enactment behavior.

Examination findings were blood pressure, 123/78 mm Hg; body mass index, 27 kg/m2; and neckcircumference, 38.6 cm (15.2 in). Nasal turbinates and septum were normal, uvula and tonsils were notenlarged, and no macroglossia or retrognathia was present. The hard palate was high-arched andnarrow. The peritonsillar lateral walls had redundant tissue.

Polysomnography (PSG) demonstrated moderate obstructive sleep apnea (OSA) with an overallapnea-hypopnea index (AHI) of 16 events/h, supine AHI of 19 events/h, and REM-sleep AHI of43 events/h (Figure 5-3). The oxygen saturation nadir was 83%. The periodic limb movement indexwas 8 per hour. The PSG was repeated for continuous positive airway pressure (CPAP) titration.The patient was fitted with a variety of masks and liked a nasal mask best. At a CPAP pressureof 9-cm water, the AHI improved to 2 events/h, supine AHI to 3 events/h, and REM-sleep AHIto 0 events/h. The oxygen saturation nadir was 94%. The periodic limb movement index was0 events/h.

After 6 weeks of using CPAP, she reported significantly improved symptoms. She initially haddifficulty falling asleep with CPAP but was now using it for 8 hours nightly with refreshing sleep

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A family history of snoring or sleep-disordered breathing can increase one’srisk of OSA, possibly because of similarcraniofacial anatomic features as well assimilar incidences of obesity amongrelatives. Behavioral risk factors forOSA include use of sedatives or alcoholand sleeping in the supine position.OSA incidence is especially high inpeople with certain medical comorbid-ities, including type 1 and type 2diabetes mellitus, polycystic ovariansyndrome, congestive heart failure,stroke, or Down syndrome.7,11Y13 Hypo-thyroidism can also exacerbate OSA.14

While frequently associated with snor-ing, chronic nasal obstruction plays arelatively minor role in the pathogene-sis of OSA, although use of intranasalsteroid medications can help to improvethe efficacy of OSA treatment.15 Neuro-logic disorders associated with an in-creased risk of sleep-disordered breathinginclude stroke, epilepsy, Parkinson dis-

ease, multiple system atrophy, and neu-romuscular disorders that weaken thediaphragm (causing hypoventilation) orpharynx (contributing to OSA), such asmyasthenia gravis or ALS (Table 5-1).16Y25

PathophysiologyMost people with OSA have normal re-spiratory patterns during wakefulnesswith appropriate feedback control sys-tems. However, changes occur duringsleep that predispose them to a sleep-disordered breathing pattern. A normalsleep-related decrease, which occurs inneuronal excitatory input to pharyngealdilator muscles, is excessively reducedamong many individuals with OSA,resulting in hypotonic pharyngeal mus-cles and increased risk of airway col-lapse.26 This abnormality may be dueto impaired sensory, cortical, or motorcomponents of the upper airway reflexthat serves to resist upper airway col-lapse in response to negative pressure

and improvedsubjective memoryand concentration.Awakenings werenow rare, and hernocturia andmorning headacheshad resolved.

Comment. Womenmay have atypicalOSA presentingsymptoms, with olderage; lower body massindex; and lowerincidence of snoring,witnessed apneas, or choking arousals. Symptoms often develop when the woman is perimenopausal.Sleep-maintenance insomniamay present similarly, but patients withOSA-suggestive features (eg, snoring,morning headaches, oropharyngeal crowding) should first undergo evaluation for sleep-disorderedbreathing. Sedative-hypnotic drugs can worsen OSA severity and are contraindicated in untreated OSA.The PSG also demonstrated mild periodic limb movements, which can be secondary to untreated OSAand frequently resolve with CPAP. OSA was moderate overall but severe during REM sleep (Figure 5-3).Isolated REM-related OSA can also occur but has an unknown impact on long-term health.

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FIGURE 5-3 Hypnogram of REM-related apnea. This hypnogram summarizes stages of sleepover the course of the night and temporally correlates them with respiratory events.As shown by the red arrows, this patient exhibits apneas and hypopneas (verticaldashes) that occur primarily during periods of REM sleep (horizontal green bars).




during inspiration.27 Sensory deficitsmay include impaired functioning ofmechanoreceptors that sense airflow,pressure, and muscle tone.28 Corticalarousability may be blunted during ap-neas, hypoxia, or hypercapnia. Motornerve dysfunction may reduce activa-tion of important pharyngeal dilatormuscles such as the genioglossus, re-sulting in pharyngeal muscle hypotoniaand increased susceptibility to airwaycollapse.27,29 Snoring-induced vibratorytrauma and mechanical strain from re-peated upper airway collapse may con-tribute to the development of irreversibleperipheral nerve injury in OSA.28,30

Anatomic factors also play a prom-inent role. People with OSA can havedifferences in upper airway soft tissuevolume and craniofacial anatomy thatresult in a narrowed pharyngeal lumen,causing abnormal increases in upper

airway pressure even while awake. Whencoupled with even a normal degree ofreduced pharyngeal muscle tone dur-ing sleep, airway obstruction occurs.31

Craniofacial factors can include a high-arched palate and insufficient pro-trusion or width of the maxilla andmandible.10 Common soft tissue fea-tures include adenotonsillar hypertro-phy, an elongated and edematous uvula,and an enlarged tongue relative tothe size of the oropharyngeal cavity(macroglossia). Obesity can significantlycontribute to soft tissue hypertrophyand narrowing of the pharyngeal space.Each of these predisposing factors maybe present to differing degrees in dif-ferent people.

SymptomsThe diagnosis of OSA is based on acombination of clinical and PSG criteria.

KEY POINT

h Obstructive sleep apneais viewed as a primarilymechanical problem ofthe upper airway, withboth neuronal andanatomic factorscontributing toincreased collapsibility.

TABLE 5-1 Mechanisms of Sleep-Disordered Breathing Induction inKey Neurologic Diseases

Neurologic DiseaseType and Presumed Mechanism ofSleep-Disordered Breathing

Acute stroke Obstructive sleep apnea (OSA): dysphagia and upperairway muscle weakness, supine positioning.19

Central sleep apnea: injury to brainstem respiratorycontrol centers, cerebral edema, impaired consciousness.20

Neuromuscular disease OSA: upper airway muscle weakness.

Central sleep apnea: weakness of chest wallmuscles and diaphragm, exacerbated bysleep-related physiologic muscle relaxation.21

Parkinson disease No clear association. OSA (when present)possibly caused by motor symptoms affectingupper airway patency at the level of the glottis.22

Multiple system atrophy OSA: respiratory stridor during sleep.

Cheyne-Stokes respirations: caused by vocalcord abductor paralysis, bulbar weakness, injuryto brainstem respiratory control neurons.23,24

Epilepsy OSA: Antiepileptic drugs can exacerbate OSA riskfactors such as obesity, increased neck circumference,and upper airway collapsibility. Vagus nervestimulators can affect respiration during sleep.25



The clinical presentation of OSA mayinclude symptoms such as snoring,apneas in sleep that are witnessed byobservers, a history of awakeningsassociated with a sensation of chokingor gasping for air, nocturia, morningheadaches, heavy diaphoresis duringsleep (especially in the upper chestand neck area), and excessive daytimesleepiness. The degree of subjectivedaytime sleepiness can be gauged usingthe Epworth Sleepiness Scale (see thearticle ‘‘Approach to and Evaluationof Sleep Disorders’’), an eight-questionmeasure of the subjective likelihood ofthe patient dozing unintentionally invarious common daytime situations.32

An Epworth Sleepiness Scale scoregreater than 10 of 24 is consistent withsubjective excessive daytime sleepiness.Screening tools such as the STOP-BANGquestionnaire or Berlin Questionnairecan also aid practitioners in assessingtheir patients’ OSA risks.33,34 Patientsmay report memory problems, irrita-ble mood, and reduced alertness andconcentration.35 People with OSA havea significantly higher risk of motorvehicle accidents because of impairedalertness or falling asleep while driving,and this risk does not necessarily cor-relate with the severity of the OSA.36

This issue can be of particular concernfor commercial drivers.37 OSA is alsoassociated with nocturnal gastroeso-phageal reflux because obstructiveevents can increase intra-abdominalpressure, which may eventually weakenlower esophageal sphincter tone.38,39

Less common symptoms include peri-odic limb movements in sleep, dreamenactment behavior, and sleepwalkingcaused by incomplete arousals trig-gered by obstructive events.40,41

Physical ExaminationSuggestive physical examination find-ings for OSA include an enlarged neckcircumference (greater than or equal to

43.2 cm [17 in] in men or greater thanor equal to 40.6 cm [16 in] in women)and obese body habitus as determinedby a BMI of greater than 30 kg/m2. Theanatomy of the face and oral cavity isalso helpful in gauging the likelihood ofdeveloping a mechanical obstructionduring sleep. One prospective studyof 420 subjects found an up to 2.6-foldincrease in the adjusted odds ratio forOSA if subjects had abnormal morpho-metric measures of the upper airway.These included narrowing of the pos-terior pharyngeal space due to im-pingement by peritonsillar tissues,tonsillar hypertrophy, macroglossia(tongue enlarged above the level ofthe mandibular occlusion plane), retro-gnathia (recessed chin), and enlargeduvula (greater than 1.5 cm [0.6 in] inlength or greater than 1.0 cm [0.4 in] inwidth).42 Such physical measures oforal cavity parameters, BMI, neck cir-cumference, and pharyngeal adiposityare strongly associated with OSA.43,44

Thus, facial morphology and orophar-yngeal examination are important partsof the OSA evaluation. The Mallampaticlassification, originally developed toassess for ease of endotracheal intuba-tion, has also been adapted to helppredict likelihood of OSA (see thearticle ‘‘Approach to and Evaluation ofSleep Disorders’’).45

PolysomnographyPatients who have history and ex-amination findings suggestive of OSAshould undergo confirmatory testingwith PSG. Full PSG combines EEG fordetermination of sleep stages, surfaceEMG to measure neck muscle tone andlimbmovements, electrooculogram forassessing eye movements, respiratoryinductance plethysmography belts formeasurement of thoracic and abdomi-nal respiratory effort, pulse oximetry,ECG, and monitors to detect snoringand airflow movement through the

KEY POINT

h Symptoms suggestive ofobstructive sleep apneainclude snoring;witnessed apneas;arousals associated withchoking, gasping, anddiaphoretic awakeningsfrom sleep; and excessivedaytime sleepiness.




nose andmouth (Figure 5-1, Figure 5-2,Figure 5-4). While PSG is typically per-formed in the sleep laboratory, this testhas also been adapted and simplifiedfor home diagnostic use, with meas-ures of airflow and oxygenation butwithout use of EEG in some circum-stances. In the appropriate clinicalcontext, home portable monitor test-ing can result in satisfactory treatmentoutcomes that are comparable to usingin-laboratory PSG.46 However, becausemost home monitors cannot distin-guish between sleep and wake states,

they tend to underestimate the severityof OSA, particularly when apneas orhypopneas are associated with arousalswithout significant oxygen desatura-tion. AASM guidelines recommendusing portable monitors for diagnosisonly in patients with a high pretestprobability of OSA and no significantmedical comorbidities.47 Further dis-cussion of home sleep testing is pro-vided in the article ‘‘In-Home Testingfor Obstructive Sleep Apnea.’’

The severity of OSA is determined bythe AHI, which is a measure of the

KEY POINT

h Polysomnography is thediagnostic modality ofchoice for obstructivesleep apnea and othersleep disorders,although monitors withfewer channels havebeen validated in certainpopulations forobstructive sleep apneadetection.

FIGURE 5-4 Polysomnographic depiction of Cheyne-Stokes respirations. A 5-minute epoch from a polysomnogram depictingCheyne-Stokes respirations, defined as three or more cycles of crescendo-decrescendo respiratory amplitudealternating with central apneas. Red curved arrows denote resumption of crescendo-decrescendo breathing

pattern. Channels from top to bottom represent EEG (left and right central, left and right occipital), electrooculogram (leftand right eyes), chin EMG, EKG, snoring, nasal pressure transducer, oral thermistor, respiratory effort (thoracic and abdominalmovement), and arterial oxygen saturation.




number of apneas and hypopneas perhour. In adults, an AHI of 5 events/h orgreater is consistent with a diagnosis ofOSA. The AHI is further gradated toquantify the degrees of severity of OSA,with an AHI between 5 events/h and14 events/h consideredmild OSA, 15 to29 events/h considered moderate OSA,and 30 events/h or greater consideredsevere OSA.

Long-Term ConsequencesMany patients are motivated to initiatetreatment for OSA due to symptomssuch as excessive daytime sleepiness,fragmented sleep, and bed partner re-ports of snoring and periods of breath-ing cessation. However, some patientsexperience no overt daytime symptomsandmay be reluctant to treat an ‘‘asymp-tomatic’’ disorder. In all instances, it isthe clinician’s responsibility to counselpatients about the serious potentialconsequences of OSA and the impor-tance of adequate treatment. Educatingpatients about the pathophysiology andconsequences of OSA, including therisks of drowsy driving, can significantlyaffect treatment adherence.48

Untreated, OSA can cause or exacer-bate a substantial number of medicalcomorbidities. Most of the sequelaestem from physiologic changes thatoccur in response to chronic apneas orhypopneas. Fragmentation of sleep dueto repeated respiratory arousals canadversely affect wake behavior, includ-ing mood, concentration, vigilance, andattention (Case 5-1).49 Intermittenthypoxia and hypercapnia over timecan increase cardiovascular risk andcause neuronal injury.50,51 OSA is alsoassociated with altered sympathetic andcatecholaminergic neuronal activity,with overcompensatory elevations inautonomic tone that increase risk ofhypertension, cor pulmonale, conges-tive heart failure, arrhythmias, andsudden death. Physiologic changes

associated with OSA also include plate-let aggregation, vascular endothelial celldysfunction, and metabolic dysregula-tion, which can increase the overallincidence of coronary artery diseaseand stroke and worsen glycemic con-trol in patients with diabetes melli-tus.50,52,53 Among patients withepilepsy, OSA can worsen seizure fre-quency if left untreated.54 It can alsoincrease the risk of developing demen-tia and exacerbate the degree of cogni-tive dysfunction in people with mildcognitive impairment.55,56

Treatment OptionsThe mainstay of treatment for OSAconsists of the delivery of positive airwaypressure (PAP) through a tightly fittedfacial mask. The pressurized air acts as apneumatic stent to maintain patencyof the upper airway during sleep. PAPtreatment typically uses room air,although supplemental oxygen may alsobe used if a concurrent pulmonaryproblem is present. Different PAPmodal-ities include CPAP, wherein a set airpressure is delivered throughout sleep;auto-CPAP, which detects variations inthe degree of obstruction and automati-cally adjusts the amount of air pressureto compensate; and bilevel PAP, whichdelivers two different air pressures witheach breath (a higher pressure duringinspiration and a lower pressure duringexpiration), noninvasively ventilating thepatient (Table 5-2). The appropriatepressure settings are typically deter-mined during a PAP titration PSG. PAPis a highly effective treatment for OSA,successfully normalizing AHI and im-proving waking symptoms in most pa-tients. It is therefore considered thecurrent treatment of choice for OSA.

Limitations of PAP treatment areprimarily related to patient discomfortor difficulty acclimating to the device.Technologic advances in delivery sys-tems have helped with some of these

KEY POINTS

h The apnea-hypopneaindex is the measureused to define theseverity of sleepapnea; 5 or greater isconsidered to beabnormal.

h Continuous positiveairway pressure usesforced air to stent theairway open and reduceobstructive events.




TABLE 5-2 Summary of Treatment Options for Sleep-Disordered Breathing

Treatment Modality Specific Treatment Indication

Positive airway pressure (PAP)Continuous positive airwaypressure (CPAP)

Obstructive sleep apnea (OSA)Central/complex sleep apnea insome cases

Bilevel PAP OSA with intolerance of CPAP pressureor aerophagia (unintentional passageof air through the lower esophagealsphincter into the stomach duringPAP treatment)

Central/complex sleep apnea,Cheyne-Stokes respirations

Obesity hypoventilation syndrome

Neuromuscular disease or diaphragmaticweakness

Adaptive servo-ventilation Central/complex sleep apnea,Cheyne-Stokes respirations

Oral appliancesTongue retaining device Mild to moderate OSA

Mandibular repositioning device Severe OSA with PAP intolerance

Soft palate lifting device Mild to moderate OSA

Positional therapy Avoidance of supine sleep Primarily positional OSA

Surgical treatmentsSeptoplasty Nasopharyngeal obstruction

Turbinate reduction

Adenoidectomy

Tonsillectomy Oropharyngeal obstruction

Uvulopalatopharyngoplasty

Midline glossectomy Hypopharyngeal obstruction

Base-of-tongue reduction

Genioglossus advancement

Hyoid suspension

Mandibular advancement

Tracheostomy Tracheal obstruction

Maxillomandibular advancement Obstruction at multiple sites

Bariatric surgery Morbid obesity

Expiratory positive airwaypressure (EPAP)

Single-use nasal EPAP Mild OSA



issues. Some newer mask styles such asthe ‘‘nasal pillows’’ interface are smallerwith less obtrusive headgear. The use ofheated humidification has helped re-duce nasal congestion and mouth dry-ness that can occur with PAP treatment.Treatment of chronic nasal congestionwith intranasal saline or steroid sprayscan also improve PAP tolerance. Forpatients with claustrophobia, gradualdesensitization programs have beenused with some success.57 Bilevel PAPmay be better tolerated by patientsrequiring higher PAP pressures and isalso an effective treatment for CSA.

For some patients, OSA is primarilypresent when sleeping in the supineposition because of mechanical changesassociated with neck positioning andgravity. The severity of their OSAimproves dramatically when sleeping inthe lateral or prone positions. For suchpatients, an effective treatment mayexclusively consist of using special pil-lows or other positioning devices tohelp them avoid supine sleep. Thisstrategy is termed positional therapy.It is associated with modest reductionsin the AHI but is less effective forsevere OSA. A concern is that treat-ment may not be completely effectivethroughout the night or that patientadherence to therapy may wane withtime. However, a recent study demon-strated a reasonable compliance of 74%and persistent efficacy in lowering AHIafter 3 months of use at home.32

Surgical treatment options for OSAconsist of a variety of procedures in-tended to reduce pharyngeal soft tissuebulk and correct nasal obstruction(Table 5-2). These range from moreaggressive surgeries, such as maxillo-mandibular advancement and uvulopa-latopharyngoplasty, to somewhat lesscomplex procedures, such as radiofre-quency ablation and soft palatalimplants.47 Tracheostomy is also usedbut is typically reserved for very severe

OSA with significant medical comorbid-ities when all other treatment optionshave been exhausted. A recent updateof AASM practice parameters reviewingstudies of surgical treatment options forOSA found varying degrees of successfor these procedures, and no oneprocedure was consistently effective.58

One of the most commonly performedprocedures, uvulopalatopharyngoplasty,appears to be more effective in mildOSA and has an approximately 40% to50% success rate.59 However, surgicalsuccess is defined by most studies as a50% reduction in baseline AHI; there-fore, the postoperative AHI may remainin the abnormal range and patients maystill have significant residual OSA.60,61

The surgical cure rate (AHI less than 5events/h) of uvulopalatopharyngoplastyis estimated at 16%.59

Other alternatives to PAP ther-apy include oral appliances, typicallyfashioned by dentists or oral surgeonsspecializing in OSA, which can be usedin some patients with mild to moderatedisease (Table 5-2).62 A variety of stylesof oral appliances are available, andmost work by repositioning the man-dible to increase forward and down-ward protrusion, thereby widening theupper airway space in the posteriorpharynx.63 A recently developed treat-ment for OSA is nasal expiratory pos-itive airway pressure (EPAP), which is asingle-use device sealed into eachnostril with adhesive. Its mechanicalvalves provide high expiratory resist-ance, creating positive airway pressureduring expiratory breaths and acting asa pneumatic splint to maintain upperairway patency.64 A multicenter, double-blind, randomized, controlled trialfound that 3 months of nasal EPAPreduced AHI by at least 50% from abaseline in the mild to low-moderateOSA range (median baseline AHI13.8 events/h to 16.7 events/h) in 51%of patients.64 Therefore, nasal EPAP may




be a useful new treatment option formild OSA, but insufficient data exist forits role in moderate to severe OSA withsignificant oxygen desaturation events.No effective pharmacologic treatment forOSA is available, and oxygen treatmentin the absence of PAP is also ineffec-tive.65 Weight loss (by either surgicalmeans or dietary and lifestyle modifi-cations) should be recommended forall obese patients with OSA and cansignificantly improve sleep-disorderedbreathing.66,67 The various treatmentoptions for sleep-disordered breathingare summarized in Table 5-2.

CENTRAL SLEEP APNEACentral apnea is defined as at least a 10-second period of loss of airflow withthe absence of respiratory effort indica-tive of a brief loss of ventilatory drive.1

During sleep, respiration is primarilydictated by partial pressure of arterialcarbon dioxide (PaCO2). There is alevel of PaCO2 below which a pause inbreathing will occur, termed the apneicthreshold.68 The apneic threshold ishigher during wake than sleep; thus, abrief central apnea may normally beobserved during the transition fromwake to sleep at sleep initiation andfollowing brief arousals, as the PaCO2

levels rise again to the level that willstimulate respiration.

The respiratory control system isregulated by pulmonary vagal receptorsand central and peripheral chemore-ceptors. Central sensors in the medullaare stimulated by hypercapnia, whileperipheral sensors in the carotid bodyare driven by both hypercapnia andhypoxia. Voluntary mechanisms com-pensate for any disruptions in thisautomated control during wakefulnessand are absent during sleep, which mayfacilitate the emergence of abnormalbreathing patterns (Case 5-2).

For instance, in heart failure, CSA candevelop because of chronic hypocapnia

related to changes in hemodynamics inthe left heart, and consequent augmen-tation of peripheral and central chemo-sensitivity. This hypersensitivity can leadto an exaggerated response to the fall inpartial pressure of arterial oxygen (PaO2)and rise in PaCO2 seen during a singleapnea, overstimulating ventilation andagain reducing PaCO2 below the apneicthreshold.69 This can lead to a cyclicpattern of hyperventilation and hypoven-tilation, known as Cheyne-Stokes respira-tions (Figure 5-4).4 Central apneas canalso be seen in other hypocapnic states,such as the periodic breathing of highaltitudes. Central apneas may also occurin the setting of hypercapnia. Medica-tions such as opiates can lead to CSA bysuppressing neuronal activity in respi-ratory brain centers.70 Diseases of brain-stem or autonomic dysfunction, suchas multiple system atrophy or lesionsof the cervical spinal cord, may be as-sociated with central apneas.

SLEEP-RELATEDHYPOVENTILATIONSleep-disordered breathing also en-compasses hypoventilation, which canbe exacerbated during sleep or mayprecede the onset of hypoventilationduring wakefulness. These conditionsinclude obesity hypoventilation syn-drome (OHS), hypoventilation due toneuromuscular disorders, medication-related hypoventilation, hypoventila-tion with brainstem dysfunction, andcentral alveolar hypoventilation.

OHS is defined as a triad of obesity(BMI of 30 kg/m2 or greater): (1) wakinghypercapnia (PaCO2 of 45 mm Hg orgreater), (2) hypoxemia (PaO2 of 70 mmHg or less), and (3) sleep-disorderedbreathing in the absence of any othercause of hypoventilation such as pul-monary disease, metabolic conditions,or neuromuscular disorders.71 Thetype of sleep-disordered breathing seenin OHS is most commonly OSA, but

KEY POINT

h A central apnea isdefined by cessation ofairflow without evidenceof respiratory effort.



10% of patients also have sleep hypo-ventilation (PaCO2 that is at least 10mm Hg greater in sleep than in wak-ing, or significant oxygen desaturationsunrelated to apneas or hypopneas).71

This syndrome is distinct from simpleobesity with OSA, in that OHS patientshave increased risk of pulmonary hyper-tension, more severe upper airway ob-struction, abnormally high mechanicalload on respiratory muscles due to adi-posity, and blunted compensatory respi-ratory drive in response to hypercapniaand hypoxia.71 Patients often presentwith typical OSA symptoms of snoring,nocturnal apneas, and excessive daytimesleepiness, but in contrast to uncompli-

cated OSA they also have concurrentdyspnea, peripheral edema, and otherphysical examination findings of corpulmonale.72 OHS is a diagnosis ofexclusion; once other causes of hypo-ventilation have been ruled out, thediagnosis is based on physical exami-nation, PSG findings, and hypercapniaon an arterial blood gas. The preferredtreatment is nocturnal CPAP, or bilevelPAP for patients with predominantlycentral hypoventilation.73

Hypoventilation is frequently seen inthe setting of neuromuscular disease as-sociatedwith decreased vital capacity andrespiratory muscle weakness. Hypoven-tilation is further exacerbated during

Case 5-2A 57-year-old man presented with a long history of snoring and disrupted sleep. He went to bedregularly between 10:00 PM and 11:00 PM, and would fall asleep quickly. He aroused briefly twice anight for nocturia and awakened at 7:30 AM. He often fell asleep unintentionally when inactive. HisEpworth Sleepiness Scale score was 15 of 24, consistent with hypersomnolence.

His medical history was notable for nonischemic cardiomyopathy, congestive heart failure withan ejection fraction of 15% to 20%, hypertension, and type 2 diabetes mellitus. His medicationsincluded carvedilol, hydralazine, lisinopril, and furosemide.

Examination findings were blood pressure, 146/70 mm Hg; heart rate, 68; height, 1.8 m (5 ft 11 in);weight, 82 kg (181 lbs); body mass index, 25.31 kg/m2. Notable findings included a crowdedoropharynx and a modified Mallampati class IV airway. No peripheral edema was present.

A diagnostic polysomnogram (PSG) demonstrated severe obstructive sleep apnea (OSA) with anapnea-hypopnea index of 40 events/h and oxyhemoglobin saturation nadir of 73%. During thecontinuous positive airway pressure (CPAP) titration PSG at CPAP levels that alleviated his obstructiveevents, significant central sleep apnea (CSA) emerged, with several prolonged episodes ofcrescendo-decrescendo breathing consistent with Cheyne-Stokes respirations (Figure 5-4).

Adaptive servo-ventilation titration PSG found that at settings of an end-expiratory pressure of 7 cmof water with variable-pressure inspiratory support, both the obstructive and central apneas improved(residual apnea-hypopnea index of 4.6 events/h) and oxyhemoglobin saturation nadir improved to 86%.At follow-up after 1 month of therapy, the patient reported a great alleviation of his hypersomnolence.

Comment. The most common condition associated with CSA is congestive heart failure. Often, theCheyne-Stokes respiratory pattern is observed. First-line therapy for this condition in the setting of heartfailure is medical optimization, as this may dramatically improve sleep-disordered breathing. However,CSA and Cheyne-Stokes respirations may persist even when the patient’s heart failure is well controlled.Severe OSA may prevent the manifestation of central apnea on PSG, and this breathing pattern may onlyemerge once CPAP therapy is initiated. The clinical significance of CPAP-emergent central apnea, alsotermed complex sleep apnea, remains controversial as it self-resolves over time in most cases. Given thispatient’s underlying heart failure, an alternate mode of pressure support was justified. Adaptiveservo-ventilation and other modes of variable pressure support use a constant end-expiratory pressure toreduce or eliminate obstructive events. On a breath-by-breath basis, they deliver varying levels ofinspiratory pressure support to maintain the tidal volume and overall minute ventilation.




sleep, especially during REM sleepwhen ventilation is driven primarily bythe diaphragm because of normalREM-related skeletal muscle atonia.Patients who are dependent on skeletalaccessory muscles of respiration mayexperience profound hypoventilationduring REM sleep, especially if there isconcurrent diaphragmatic weaknesssuch as in ALS.74 Symptoms can in-clude excessive daytime sleepiness,headaches, and poor sleep quality withnightmares and enuresis.75 Treatmentwith noninvasive mechanical ventila-tion modalities such as bilevel PAPcan alleviate symptoms in the shortterm and may prolong survival in pa-tients with motor neuron diseases.75

Chronic opioid medication use canalso result in sleep hypoventilation.Opioids binding to CNS receptors impaircentral respiratory control centers, withensuing central apnea, hypoventilation,or ataxic breathing pattern.70,76 Patientson long-term opioid treatment have agreater risk of hypoxemia in sleep thatis independent of apneas or hypopneas.Treatment consists of PAP, particularlybilevel PAP with a backup rate in pa-tients with significant central apneas orhypoventilation.77 CPAP can be effectivebut may exacerbate central apneas; useof adaptive servo-ventilation (ASV) iscontroversial in this setting and requiresfurther study.

Hypoventilation may ensue afterbrainstem or spinal cord injury becauseof lesions to neural pathways control-ling diaphragm, chest, and abdominalmuscles.78 Hypotonia of respiratorymuscles can result in a restrictive ven-tilatory defect with hypercapnia andhypoxia and increased work of breath-ing. This can lead to alveolar hypoven-tilation that is exacerbated duringsleep, especially REM sleep. Diagnostictests include arterial blood gas analysisand PSG. Optimal treatment consists ofnoninvasive positive pressure ventila-

tion, particularly bilevel PAP with orwithout a backup rate.78,79

Another condition characterized bycentral events is central alveolar hypo-ventilation, which comes in two forms,acquired and congenital. Acquired cen-tral alveolar hypoventilation may beseen following injury to the respiratorycenters in the medulla, for instancefrom trauma, encephalitis, neoplasms,or stroke. A much rarer, congenital,central hypoventilation syndrome typi-cally presents in the first year of life withhypoxia, hypercapnia, and prolongedcentral apneas during sleep, although alate-onset form has been described inadults.80,81 This condition is caused bytrinucleotide expansion mutations inthe PHOX2B gene, a transcriptionfactor regulating development of theautonomic nervous system.82

Several options are available for treat-ment of central sleep apnea.83 CPAP,bilevel PAP, and other ventilator sup-port modalities, such as ASV, have beenextensively studied (Table 5-2). CPAPmay improve left ventricular ejectionfraction and, if titrated to adequatelytreat the sleep-disordered breathing,improves survival. One caveat to thisis that most studies were done beforethe widespread use of spironolactoneor beta-blockers for treatment of heartfailure; patients on these more effectivemedications may therefore show asmaller magnitude of cardiac improve-ment with CPAP. ASV or bilevel PAP (inspontaneous mode with patient-triggeredbreaths, or with an automated backuprespiratory rate) have similarly benefi-cial effects on cardiac function and maybe used to improve comfort if higherlevels of CPAP pressure are needed,or to improve ventilation in hyper-carbia. The use of supplemental oxygenis typically limited to patients with CSAwho are unable to comply with PAPtherapy. Also, the use of acetazolamide,a carbonic anhydrase inhibitor, induces

KEY POINT

h Central sleep apnea canbe seen in a variety ofconditions, includingcongestive heart failure,medullary lesions, andautonomic dysregulation.



a metabolic acidosis that may lead to adecrease in central apnea frequency,although the evidence is much weakerfor its effectiveness when compared toeither oxygen or PAP.55

CONCLUSIONSleep-disordered breathing is a highlyprevalent disorder and can occur co-morbid to many medical and neurologicconditions. Untreated, it may signifi-cantly affect daytime alertness andconcentration; increase risk of cardio-vascular events, such as stroke, ar-rhythmia, or myocardial infarction;worsen hypertension; exacerbatemooddisorders; and interfere with optimalseizure control. PAP, the first-line treat-ment option, is safe and effective innormalizing breathing during sleep.Other treatment options include craniofa-cial or upper airway surgery, oral ap-pliances, and weight loss. Effectivetreatment of sleep-disordered breathingcan reduce symptoms of excessive day-time sleepiness, snoring, and fragmentedsleep andmay improve health outcomes.

REFERENCES1. Iber C, Ancoli-Israel S, Chesson A, Quan SF.

The AASM manual for the scoring of sleepand associated events: rules, terminology,and technical specifications. Westchester, IL:American Academy of Sleep Medicine, 2007.

2. American Academy of Sleep Medicine.International classification of sleepdisorders, second edition: diagnostic andcoding manual. Westchester, IL: AmericanAcademy of Sleep Medicine, 2005.

3. Martin SE, Engleman HM, Kingshott RN,Douglas NJ. Microarousals in patients withsleep apnoea/hypopnoea syndrome. J SleepRes 1997;6(4):276Y280.

4. Jordan AS, White DP, Lo YL, et al. Airwaydilator muscle activity and lung volumeduring stable breathing in obstructive sleepapnea. Sleep 2009;32(3):361Y368.

5. Huang J, Zhang J, Lam SP, et al. Ameliorationof obstructive sleep apnea in REM sleepbehavior disorder: implications for theneuromuscular control of OSA. Sleep 2011;34(7):909Y915.

6. Young T, Palta M, Dempsey J, et al. Theoccurrence of sleep-disordered breathingamong middle-aged adults. N Engl J Med1993;328(17):1230Y1235.

7. Lee W, Nagubadi S, Kryger MH, et al.Epidemiology of obstructive sleep apnea: apopulation-based perspective. Expert RevRespir Med 2008;2(3):349Y364.

8. Li Y, Veasey SC. Neurobiology andneuropathophysiology of obstructive sleepapnea. Neuromolecular Med 2012;14(3):168Y179.

9. Mehra R, Stone KL, Blackwell T, et al.Prevalence and correlates of sleep-disorderedbreathing in older men: osteoporoticfractures in men sleep study. J Am GeriatrSoc 2007;55(9):1356Y1364.

10. Sutherland K, Lee RW, Cistulli PA. Obesityand craniofacial structure as risk factorsfor obstructive sleep apnoea: impactof ethnicity. Respirology 2012;17(2):213Y222.

11. Schober AK, Neurath MF, Harsch IA.Prevalence of sleep apnoea in diabeticpatients. Clin Respir J 2011;5(3):165Y172.

12. van Dijk M, Donga E, van Dijk JG, et al.Disturbed subjective sleep characteristics inadult patients with long-standing type 1diabetes mellitus. Diabetologia 2011;54(8):1967Y1976.

13. Dyken ME, Lin-Dyken DC, Poulton S, et al.Prospective polysomnographic analysis ofobstructive sleep apnea in down syndrome.Arch Pediatr Adolesc Med 2003;157(7):655Y660.

14. Resta O, Pannacciulli N, Di Gioia G, et al.High prevalence of previously unknownsubclinical hypothyroidism in obese patientsreferred to a sleep clinic for sleep disorderedbreathing. Nutr Metab Cardiovasc Dis2004;14(5):248Y253.

15. Kohler M, Bloch KE, Stradling JR. The role ofthe nose in the pathogenesis of obstructivesleep apnoea and snoring. Eur Respir J2007;30(6):1208Y1215.

16. Perrin C, D’Ambrosio C, White A, Hill NS.Sleep in restrictive and neuromuscularrespiratory disorders. Semin Respir Crit CareMed 2005;26(1):117Y130.

17. Manni R, Terzaghi M. Comorbidity betweenepilepsy and sleep disorders. Epilepsy Res2010;90(3):171Y177.

18. Gaig C, Iranzo A. Sleep-disordered breathingin neurodegenerative diseases. Curr NeurolNeurosci Rep 2012;12(2):205Y217.

19. Johnson KG, Johnson DC. Frequency ofsleep apnea in stroke and TIA patients: a

KEY POINT

h Successful treatment ofcentral sleep apneaassociated with heartfailure is associated withimproved cardiacfunction and survival.




meta-analysis. J Clin Sleep Med 2010;6(2):131Y137.

20. Bassetti CL. Sleep and stroke. Semin Neurol2005;25(1):19Y32.

21. Arnulf I, Similowski T, Salachas F, et al. Sleepdisorders and diaphragmatic function inpatients with amyotrophic lateral sclerosis.Am J Respir Crit Care Med 2000;161(3 pt 1):849Y856.

22. Schulte EC, Winkelmann J. When Parkinson’sdisease patients go to sleep: specific sleepdisturbances related to Parkinson’s disease.J Neurol 2011;258(suppl 2):S328YS335.

23. Shimohata T, Shinoda H, Nakayama H, et al.Daytime hypoxemia, sleep-disorderedbreathing, and laryngopharyngeal findingsin multiple system atrophy. Arch Neurol2007;64(6):856Y861.

24. Benarroch EE, Schmeichel AM, Low PA, et al.Depletion of putative chemosensitiverespiratory neurons in the ventral medullarysurface in multiple system atrophy. Brain2007;130(pt 2):469Y475.

25. van Golde EG, Gutter T, de Weerd AW. Sleepdisturbances in people with epilepsy;prevalence, impact and treatment. SleepMed Rev 2011;15(6):357Y368.

26. Tangel DJ, Mezzanotte WS, White DP.Influence of sleep on tensor palatini EMGand upper airway resistance in normal men.J Appl Physiol 1991;70(6):2574Y2581.

27. Broderick M, Guilleminault C. Neurologicalaspects of obstructive sleep apnea. Ann N YAcad Sci 2008;1142:44Y57.

28. Guilleminault C, Huang YS, Kirisoglu C,Chan A. Is obstructive sleep apnea syndromea neurological disorder? A continuouspositive airway pressure follow-up study.Ann Neurol 2005;58(6):880Y887.

29. Horner RL, Innes JA, Guz A. Reflexpharyngeal dilator muscle activation bystimuli of negative airway pressure in awakeman. Sleep 1993;16(8 suppl):S85YS86.

30. Saboisky JP, Butler JE, Gandevia SC, EckertDJ. Functional role of neural injury inobstructive sleep apnea. Front Neurol2012;3:95.

31. Isono S, Remmers JE, Tanaka A, et al.Anatomy of pharynx in patients withobstructive sleep apnea and in normalsubjects. J Appl Physiol 1997;82(4):1319Y1326.

32. Johns MW. A new method for measuringdaytime sleepiness: the Epworth SleepinessScale. Sleep 1991;14(6):540Y545.

33. Chung F, Subramanyam R, Liao P, et al. HighSTOP-Bang score indicates a high probabilityof obstructive sleep apnoea. Br J Anaesth2012;108(5):768Y775.

34. Kang K, Park KS, Kim JE, et al. Usefulness ofthe Berlin Questionnaire to identify patientsat high risk for obstructive sleep apnea: apopulation-based door-to-door study[published online ahead of print September29, 2012]. Sleep Breath 2012. doi:10.1007/s11325-012-0767-2.

35. Jackson ML, Howard ME, Barnes M.Cognition and daytime functioning insleep-related breathing disorders. ProgBrain Res 2011;190:53Y68.

36. Ellen RL, Marshall SC, Palayew M, et al.Systematic review of motor vehicle crash riskin persons with sleep apnea. J Clin SleepMed 2006;2(2):193Y200.

37. George CF. Sleep apnea, alertness, andmotor vehicle crashes. Am J Respir Crit CareMed 2007;176(10):954Y956.

38. Emilsson OI, Janson C, Benediktsdottir B,et al. Nocturnal gastroesophageal reflux,lung function and symptoms of obstructivesleep apnea: results from an epidemiologicalsurvey. Respir Med 2012;106(3):459Y466.

39. Shepherd K, Hillman D, Holloway R,Eastwood P. Mechanisms of nocturnalgastroesophageal reflux events inobstructive sleep apnea. Sleep Breath2011;15(3):561Y570.

40. Iranzo A, Santamaria J. Severe obstructivesleep apnea/hypopnea mimicking REM sleepbehavior disorder. Sleep 2005;28(2):203Y206.

41. Remulla A, Guilleminault C. Somnambulism(sleepwalking). Expert Opin Pharmacother2004;5(10):2069Y2074.

42. Schellenberg JB, Maislin G, Schwab RJ.Physical findings and the risk for obstructivesleep apnea. The importance oforopharyngeal structures. Am J Respir CritCare Med 2000;162(2 pt 1):740Y748.

43. Kushida CA, Efron B, Guilleminault C. Apredictive morphometric model for theobstructive sleep apnea syndrome. AnnIntern Med 1997;127(8 pt 1):581Y587.

44. Li Y, Na L, Ye J, et al. Upper airway fat tissuedistribution differences in patients withobstructive sleep apnea and controls as wellas its effect on retropalatal mechanicalloads. Respir Care 2012;57(7):1098Y1105.

45. Mallampati SR, Gatt SP, Gugino LD, et al. Aclinical sign to predict difficult trachealintubation: a prospective study. Can AnaesthSoc J 1985;32(4):429Y434.



46. Kuna ST, Gurubhagavatula I, Maislin G, et al.Noninferiority of functional outcome inambulatory management of obstructivesleep apnea. Am J Respir Crit Care Med2011;183(9):1238Y1244.

47. Epstein LJ, Kristo D, Strollo PJ Jr, et al.Clinical guideline for the evaluation,management and long-term care ofobstructive sleep apnea in adults. J ClinSleep Med 2009;5(3):263Y276.

48. Bollig SM. Encouraging CPAP adherence:it is everyone’s job. Respir Care 2010;55(9):1230Y1239.

49. Sforza E, Haba-Rubio J, De Bilbao F, et al.Performance vigilance task and sleepiness inpatients with sleep-disordered breathing.Eur Respir J 2004;24(2):279Y285.

50. Shamsuzzaman AS, Gersh BJ, Somers VK.Obstructive sleep apnea: implications forcardiac and vascular disease. JAMA2003;290(14):1906Y1914.

51. Zhu Y, Fenik P, Zhan G, et al. Selective loss ofcatecholaminergic wake active neurons ina murine sleep apnea model. J Neurosci2007;27(37):10060Y10071.

52. Trombetta IC, Somers VK, Maki-Nunes C,et al. Consequences of comorbid sleep apneain the metabolic syndromeVimplications forcardiovascular risk. Sleep 2010;33(9):1193Y1199.

53. Redline S, Yenokyan G, Gottlieb DJ, et al.Obstructive sleep apnea-hypopnea andincident stroke: the Sleep Heart Health Study.Am J Respir Crit Care Med 2010;182(2):269Y277.

54. Vaughn BV, D’Cruz OF. Sleep and epilepsy.Semin Neurol 2004;24(3):301Y313.

55. Yaffe K, Laffan AM, Harrison SL, et al.Sleep-disordered breathing, hypoxia, andrisk of mild cognitive impairment anddementia in older women. JAMA 2011;306(6):613Y619.

56. Kim SJ, Lee JH, Lee DY, et al. Neurocognitivedysfunction associated with sleep qualityand sleep apnea in patients with mildcognitive impairment. Am J GeriatrPsychiatry 2010;19(4):374Y381.

57. Means MK, Edinger JD. Graded exposuretherapy for addressing claustrophobicreactions to continuous positive airwaypressure: a case series report. Behav SleepMed 2007;5(2):105Y116.

58. Aurora RN, Casey KR, Kristo D, et al. Practiceparameters for the surgical modifications ofthe upper airway for obstructive sleep apneain adults. Sleep 2010;33(10):1408Y1413.

59. Holty JE, Guilleminault C. Surgical optionsfor the treatment of obstructive sleepapnea. Med Clin North Am 2010;94(3):479Y515.

60. Hobson JC, Robinson S, Antic NA, et al. Whatis ‘‘success’’ following surgery for obstructivesleep apnea? The effect of differentpolysomnographic scoring systems.Laryngoscope 2012;122(8):1878Y1881.

61. Caples SM, Rowley JA, Prinsell JR, et al.Surgical modifications of the upper airwayfor obstructive sleep apnea in adults: asystematic review and meta-analysis. Sleep2010;33(10):1396Y1407.

62. Krishnan V, Collop NA, Scherr SC. Anevaluation of a titration strategy forprescription of oral appliances forobstructive sleep apnea. Chest 2008;133(5):1135Y1141.

63. Chan AS, Lee RW, Cistulli PA. Dentalappliance treatment for obstructive sleepapnea. Chest 2007;132(2):693Y699.

64. Berry RB, Kryger MH, Massie CA. A novelnasal expiratory positive airway pressure(EPAP) device for the treatment ofobstructive sleep apnea: a randomizedcontrolled trial. Sleep 2011;34(4):479Y485.

65. Morgenthaler TI, Kapen S, Lee-Chiong T,et al. Practice parameters for the medicaltherapy of obstructive sleep apnea. Sleep2006;29(8):1031Y1035.

66. Anandam A, Akinnusi M, Kufel T, et al.Effects of dietary weight loss on obstructivesleep apnea: a meta-analysis [publishedonline ahead of print February 29, 2012].Sleep Breath 2012. doi:10.1007/s11325-012-0677-3.

67. Greenburg DL, Lettieri CJ, Eliasson AH.Effects of surgical weight loss on measuresof obstructive sleep apnea: a meta-analysis.Am J Med 2009;122(6):535Y542.

68. Malhotra A, Owens RL. What is central sleepapnea? Respir Care 2010;55(9):1168Y1178.

69. Yumino D, Bradley TD. Central sleep apneaand Cheyne-Stokes respiration. Proc AmThorac Soc 2008;5(2):226Y236.

70. Walker JM, Farney RJ, Rhondeau SM, et al.Chronic opioid use is a risk factor for thedevelopment of central sleep apnea andataxic breathing [erratum published in J ClinSleep Med 2007;3(6):table of contents].J Clin Sleep Med 2007;3(5):455Y461.

71. Mokhlesi B. Obesity hypoventilationsyndrome: a state-of-the-art review. RespirCare 2010;55(10):1347Y1362; discussion1363Y1365.




72. Chau EH, Lam D, Wong J, et al. Obesityhypoventilation syndrome: a review ofepidemiology, pathophysiology, andperioperative considerations.Anesthesiology 2012;117(1):188Y205.

73. Borel JC, Tamisier R, Gonzalez-Bermejo J,et al. Noninvasive ventilation in mildobesity hypoventilation syndrome: arandomized controlled trial. Chest 2012;141(3):692Y702.

74. Vazquez-Sandoval A, Huang EJ, Jones SF.Hypoventilation in neuromuscular disease.Semin Respir Crit Care Med 2009;30(3):348Y358.

75. Annane D, Orlikowski D, Chevret S, et al.Nocturnal mechanical ventilation for chronichypoventilation in patients with neuromuscularand chest wall disorders. Cochrane DatabaseSyst Rev 2007(4):CD001941.

76. Yue HJ, Guilleminault C. Opioid medicationand sleep-disordered breathing. Med ClinNorth Am 2010;94(3):435Y446.

77. Guilleminault C, Cao M, Yue HJ, Chawla P.Obstructive sleep apnea and chronic opioiduse. Lung 2010;188(6):459Y468.

78. Castriotta RJ, Murthy JN. Hypoventilationafter spinal cord injury. Semin Respir CritCare Med 2009;30(3):330Y338.

79. Selim BJ, Junna MR, Morgenthaler TI.Therapy for sleep hypoventilation andcentral apnea syndromes. Curr Treat OptionsNeurol 2012;14(5):427Y437.

80. Patwari PP, Carroll MS, Rand CM, Kumar R,Harper R, Weese-Mayer DE. Congenitalcentral hypoventilation syndrome and thePHOX2B gene: a model of respiratory andautonomic dysregulation. Respir PhysiolNeurobiol 2012;173(3):322Y335.

81. Healy F, Marcus CL. Congenital centralhypoventilation syndrome in children.Paediatr Respir Rev 2011;12(4):253Y263.

82. Eckert DJ, Jordan AS, Merchia P, Malhotra A.Central sleep apnea: pathophysiology andtreatment. Chest 2007;131(2):595Y607.

83. Aurora RN, Chowdhuri S, Ramar K, et al.The treatment of central sleep apneasyndromes in adults: practice parameterswith an evidence-based literature reviewand meta-analyses. Sleep 2012;35(1):17Y40.



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