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Upper Airway Resistance Syndrome

PCCSU Volume 25, Lesson 13

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Olukayode Ogunrinde, MD; Herbert J. Yue, MD; and Christian Guilleminault, MD, BiolD

Dr. Ogunrinde is Clinical Fellow, Department of Sleep Medicine, Stanford University; Dr. Yue is Clinical Fellow, Department of Sleep Medicine, Stanford University; and Dr. Guilleminault is Professor, Division of Sleep Medicine, Stanford University Medical School, Redwood City, California.

Drs. Ogunrinde, Yue, and Guilleminault have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Identify the demographics of previously described patients with upper airway resistance syndrome (UARS).
  2. Describe the polysomnographic findings in UARS, including markers of increased respiratory effort.
  3. Discuss the clinical symptoms of UARS and their link to functional somatic syndromes.
  4. Describe the EEG findings during a respiratory event in UARS.
  5. Identify the current treatment options for UARS, as well as the benefits and risks of each.

Key words: cyclical alternating pattern; sleep-disordered breathing; upper airway resistance syndrome

Abbreviations: CAP = cyclical alternating pattern; CPAP = continuous positive airway pressure; LAUP = laser-assisted uvuloplasty; MSLT = multiple sleep latency testing; NREM = nonrapid eye movement; OHS = obstructive hypopnea syndrome; OSAS = obstructive sleep apnea syndrome; Pes = esophageal pressure; REM = rapid eye movement; RERA = respiratory effort-related arousal; UARS = upper airway resistance syndrome

Professional Practice Gap

Over the past few years, numerous articles have been published that have increased our understanding of the features of upper airway resistance syndrome (UARS). UARS has been previously described as a distinct clinical syndrome, although there is ongoing controversy and some consider it to be part of a spectrum of sleep-disordered breathing that includes primary snoring, obstructive hypopnea syndrome (OHS), and obstructive sleep apnea syndrome (OSAS). However, patients with UARS present with different polysomnographic abnormalities and do not meet generally accepted criteria for either apneas or hypopneas. The lack of education about UARS in the medical community has allowed these patients to go undiagnosed and untreated. Increased research into UARS will help us to identify the optimal treatment for these patients, as well as to educate clinicians about this relatively under-recognized population.

Introduction

UARS is characterized by abnormal respiratory effort, nasal airflow limitation, absence of obstructive sleep apnea, minimal pulse oximetry fluctuation with oxygen saturation nadirs ≥92%, and frequent nocturnal arousals or reflex brainstem activation.1 It was first recognized in children in 1982, although the term UARS was not used until the first adult cases were reported in 1993.2,3 The incidence and prevalence of UARS has been systematically investigated in a recent São Paulo epidemiologic study4 (discussed below in “Epidemiologic Studies of UARS”). Prior to the São Paulo study, some have reported prevalence rates of 8% to 20% in the literature.5,6 We now know that this syndrome has recognizable clinical and polysomnographic characteristics that differ from those observed in patients with OHS/OSAS. UARS occurs in all age groups without any clear sex preferences, although some studies suggest that women may be at increased risk. UARS has the potential for significant impact on the daytime functioning and quality of life in untreated patients and there is growing evidence to suggest that symptoms are progressive without treatment.

Pathophysiology

Sleep-disordered breathing affects multiple aspects of the upper airway and respiratory tract, including the nasal passage, nasopharynx, oropharynx, hypopharynx, and supraglottic larynx. In these patients (primarily those with OSAS), multiple changes to the control of the upper airway have been described, including development of lesions in the soft tissue and changes in the upper airway dilator muscles, all in response to repetitive airway obstruction.7 Histologic studies have demonstrated significant abnormalities in biopsy samples taken from the palate and posterior pharynx. The most consistent finding has been evidence of a neurogenic lesion, with progressive abnormalities identical to those associated with a polyneuropathy.8,9 In patients with OSAS, poor responses to airway collapse or instability are often seen and thought to be related to blunting of the afferent upper airway receptors. In contrast to patients with OSAS, similar lesions have not been described in those with UARS. In a study of 45 subjects evenly divided into one group with OSAS, one group with UARS, and a control group, no significant sensory differences in palatal two-point discrimination were seen between control individuals and those with UARS.10 Of note, those with OSAS were observed to have significant decrements in their palatal two-point discrimination, consistent with the prior findings of neurogenic lesions. Other contributors to the pathophysiology of UARS include an increase in airway collapsibility owing to abnormal inspiratory and expiratory airflow dynamics.11,12 Increased nasal airflow resistance has also been thought to contribute to the breathing impairment seen in UARS, with frequent clinical findings of collapsible nasal valves, enlarged nasal turbinates, a deviated septum, or a combination of these findings in UARS patients.13

Epidemiologic Studies of UARS

The only known epidemiologic study of UARS has been one performed as part of an epidemiologic study of sleep disorders in the city of São Paulo, Brazil, in 2007. The São Paulo Sleep Epidemiologic Study is a population-based, cross-sectional study of sleep disturbances and their risk factors.4 Methodological details of the São Paulo Epidemiologic Sleep Study are published. A total of 1,042 volunteers underwent polysomnography at the Sleep Institute of the Federal University of São Paulo; the refusal rate was a very low 5.4%. The criteria used for scoring for UARS were those described by Bao and Guilleminault.14 Polysomnography was performed according to American Academy of Sleep Medicine guidelines.15 The prevalence of UARS for the total sample was 15.5%. It was higher in women (21.87% vs 15.19%) and also in people aged <40 years (31.04% vs 5.49%).

Clinical Features

Patients with UARS have symptoms similar to those seen in OSAS, although there are some distinct features. Much of the research performed has attempted to identify and describe a group of patients with significant daytime sleepiness and disrupted sleep, but without the other dominant clinical features seen in OSAS. Typical symptoms reported by patients with UARS include excessive daytime sleepiness, fatigue, difficulty concentrating, morning headaches, and unrefreshing sleep. There can be also be a significant impairment in daytime functioning; a recent study demonstrated that subjects with UARS performed worse than patients with obstructive sleep apnea hypopnea syndrome and normal control individuals on different aspects of the Psychomotor Vigilance Task.16 In a separate study, upwards of 30% of subjects with UARS had abnormal sleep-onset latency on the Maintenance of Wakefulness Test.17 Individuals with abnormal airway anatomy are at increased risk, including those with a decreased retrolingual space, narrow nasal passages, or a small neck circumference.6 Patients are typically not obese, with a mean BMI often <25 kg/m2.3 They are also usually younger than those in whom OSAS is diagnosed, with a mean age of approximately 38 years.3 Snoring is not a requisite symptom, with 10% to 15% or more of patients having never or only intermittently snored.3,18

Patients with UARS are also more likely to report symptoms of frequent nocturnal awakening with difficulty falling back to sleep.19 This is thought to be a potential reason for increased complaints of insomnia amongst patients with UARS, including sleep onset and sleep maintenance problems. In addition to difficulties with acute insomnia, patients with UARS also have an increased likelihood of carrying a diagnosis of chronic insomnia. Other notable complaints include parasomnias, especially sleepwalking, sleep talking, and sleep terrors.20 Patients may also have symptoms of abnormal autonomic function, including lightheadedness or dizziness on rising from a supine or sitting position, cold hands and feet, and low resting blood pressures (defined as a systolic BP <105 mm Hg with a diastolic BP <65 mm Hg). In a study of 400 patients with UARS, more than 20% met criteria for low BP, a significantly higher prevalence when compared with people who have OSAS (0.6%) or insomnia (0.9%).21 Interestingly, all subjects in the study had evidence of a small oral cavity on examination with a narrowed airway space dimension on cephalometric radiographs, consistent with other reports.22 Lastly, patients with UARS have increased rates of symptoms such as gastroesophageal reflux, muscular pain, diarrhea, abdominal pain, depression, and anxiety. This has led some authors to suggest a link between UARS and functional somatic syndromes, such as irritable bowel syndrome, chronic fatigue syndrome, and fibromyalgia. In a study of 75 subjects equally divided into three groups (UARS, mild to moderate OSAS, and severe OSAS), those with UARS were more likely to report symptoms of headache, irritable bowel symptoms, and sleep-initiation insomnia.23 Subjects with UARS were also more likely to have alpha intrusion during slow-wave sleep, a polysomnographic finding described in a number of fatigue syndromes.24 In children with UARS, symptoms consistent with attention deficit disorder or attention deficit hyperactivity disorder may be present, with behavioral changes leading to poor school performance.25 Table 1 lists symptoms associated with UARS.

 


Table 1Clinical Features Associated With UARS

Daytime symptoms Excessive daytime sleepiness
  Fatigue
  Morning headaches
  Myalgias
  Difficulty concentrating
Sleep disturbances Frequent nocturnal awakenings
  Difficulties initiating sleep
  Insomnia
  Bruxism
  Restless leg syndrome
  Unrefreshing sleep
Autonomic nervous system Hypotension
  Orthostasis
  Cold hands and feet
Functional somatic syndrome associations Depression
  Anxiety
  Chronic fatigue syndrome
  Irritable bowel syndrome
  Fibromyalgia
Polysomnographic abnormalities Increased RERAs
  Increased nocturnal arousals
  Increased CAP rate
  Alpha intrusion during sleep

 

Diagnosis

Patients with UARS can present with a constellation of generalized and/or specific symptoms and a clinical examination often demonstrates craniofacial abnormalities. As noted previously, many of the prior difficulties in making a diagnosis of UARS arose because these patients do not meet polysomnographic criteria for OSAS. In the original description of UARS back in 1991, repetitive increases in upper airway resistance associated with arousals were observed in 15 subjects, defined as an increase in the peak inspiratory esophageal pressure that immediately preceded a transient arousal.3 A diagnosis of UARS requires patient symptoms, evidence of upper airway narrowing or craniofacial abnormalities, and appropriate associated polysomnographic findings. When an overnight polysomnogram is performed on a patient with UARS, there are no apneas with a hypopnea index <5, the oxygen saturation is usually >92%, and there is evidence of respiratory effort-related arousals (RERAs). Flow limitation can also be present, identified as an abnormal contour in the nasal pressure transducer signal waveform.3,14 Other techniques have been used to detect the subtle changes in respiration, such as the oral/nasal thermistor, pneumotachograph, quantitative respiratory plethysmography, and nasal cannula/pressure transducer, although measurement of esophageal pressure (Pes), or esophageal manometry, remains the gold standard.26,27

Typically, a pediatric feeding tube is used in the measurements of esophageal pressure during sleep. A number of characteristic Pes patterns associated with RERAs have been described.28,29 Pes crescendo (Fig 1) is a progressive increase in negative peak inspiratory pressure with each breath that terminates with an EEG arousal, typically a burst of alpha or delta activity. Other changes include sustained continuous respiratory effort; the Pes tracing shows a stable and persistently abnormal negative peak inspiratory pressure, different from the baseline pressure and present for more than four breaths. In both instances, the increase in respiratory effort is not usually associated with oxyhemoglobin desaturation and there may be a flattening in the nasal pressure transducer waveform, consistent with flow limitation (Figs 2, 3). The termination of both Pes crescendo and flow limitation is called Pes reversal, which is a decrease in respiratory effort indicated by a less negative peak inspiratory pressure, often without an associated EEG arousal (Fig 4). Heart rate variability is often seen during events of increased respiratory effort. Patients with UARS may also have more negative peak inspiratory pressure during nonrapid eye movement (NREM) sleep, especially slow-wave sleep, as compared with rapid eye movement sleep.30 Patients with UARS have also been described to have less NREM (both stage 1 and stage 2) sleep and more slow-wave sleep when compared with other patients with sleep-disordered breathing, although no significant difference in arousal threshold was seen.31


Figure 1. Pes crescendo. Note the esophageal pressure recording at the bottom of the tracing.

 


L13Fig2

Figure 2. Flow limitation on a polysomnogram. Note the association between CAP, with phase A2 and A345 indicative of sleep disruption, and the continuous flow limitation seen on the nasal cannula recording (duration of sample, 5 min).

 


L13Fig3

Figure 3. Flow limitation on polysomnogram monitored at slow speed (duration of sample, 30 s) Note the abnormal shape of the nasal cannula pressure transducer flow curve, with disappearance of the normal “round” curve with each breath. Note also the downward movement of the finger plethysmography (finger PPG) over-curve indicating sympathetic brainstem activation. Simultaneously, the EEG (right side of figure) changes to lower amplitude and faster frequency, indicative of a short arousal response.

 


L13Fig4

Figure 4. Pes reversal. Note the esophageal pressure recording at the bottom of the tracing.

 


Patients with UARS may also have characteristic changes in their EEG patterns during sleep. As noted previously, prior studies have shown that subjects with UARS have increased amounts of alpha frequency on EEG when compared with patients who have either OSAS or OHS.32,33 Other investigations using power spectrum EEG analysis have demonstrated that UARS patients have more theta and low alpha powers (7 to 9 Hz) during NREM sleep and more delta power during rapid eye movement sleep.29 Although an arousal is frequently seen following termination of an event associated with increased respiratory effort (ie, Pes crescendo or continuous increased respiratory effort), studies have shown that Pes reversal can occur in the absence of any clear arousal. In a study of 15 patients with UARS, a spectral analysis was performed on EEG data from central leads. The authors noted EEG changes in association with Pes events, including an increase in delta frequency activity prior to Pes reversal, and with increases in other frequencies after the event, suggesting that significant EEG changes are occurring with Pes events, even when an arousal is not visible.29

Lastly, patients with UARS have evidence of increased rates of the cyclical alternating pattern (CAP) on EEG. CAPs are a well-described pattern of NREM sleep, defined as electrocortical events that are distinct from background EEG activity and occur with a periodicity.34 An increase in CAP frequency is generally associated with sleep instability/disturbance and CNS hyperactivity and has been observed in a number of conditions, including sleep-disordered breathing, restless leg syndrome, and insomnia.31 In a study of 30 patients with UARS, increased CAP rates were seen in addition to more EEG arousals and higher markers of sleep disruption and transition (A2 and A3 indices of CAP).35 More importantly, the CAP rate was correlated with daytime symptoms of sleepiness and fatigue. This finding suggests that normalization of the breathing events in patients with UARS/sleep-disordered breathing may not be sufficient to fully treat their daytime symptoms and that addressing EEG abnormalities is important as well.

Treatment

The optimal treatment for patients with UARS is not currently known. Continuous positive airway pressure (CPAP) has been quite useful in the treatment of sleep-disordered breathing and there are some notable positive results in CPAP treatment of UARS. In a study of 15 heavy snorers with clinical evidence of UARS, treatment with nasal CPAP was associated with decreases in observed nocturnal arousals on polysomnography and decreases in mean sleep latency times on multiple sleep latency testing (MSLT) after several nights of treatment.3,36 A follow-up study of 15 subjects (in the original description of UARS) with daytime sleepiness and fatigue and who had undergone a therapeutic trial of positive pressure therapy reported similar findings.3 After treatment with approximately a month of nasal CPAP, significant improvements were seen in mean sleep latency times on MSLT (5.3 minutes vs 13.5 minutes), Pes nadir pressure (–33.1 cm H2O vs –5.3 cm H2O), amount of slow-wave sleep (1.2% vs 9.7%), and EEG arousals (31.3 vs 7.9 events/hour of sleep). Along with an improvement in sleep latency times on MSLT, there were subjective reports of improved daytime symptoms. Lastly, in a study of 130 postmenopausal women with chronic insomnia and evidence of UARS (n=62) or normal breathing (n=68), treatment with either nasal turbinectomy or nasal CPAP was associated with improvements in subjective reports of sleep quality as measured with a visual analog scale as well as mean sleep latency times on polysomnography.19 Despite the growing body of evidence supporting the use of positive pressure therapy for UARS patients, it remains difficult to obtain therapy. In a follow-up study of more than 90 patients conducted 4 to 5 years after the initial diagnosis of UARS was made, none of the subjects were receiving CPAP treatment; the main rationale given was that their insurance provider declined to provide the necessary equipment.1 Formal follow-up clinical evaluations of these patients noted significant worsening in their sleep-related complaints, with increased reports of fatigue, insomnia, and depressive mood. More disturbingly, prescriptions for hypnotics, stimulants, and antidepressants increased more than fivefold.

Other interventions, such as surgery or oral appliances, have also been used with some success in the treatment of patients with UARS. Procedures such as uvulopalatopharyngoplasty, laser-assisted uvuloplasty (LAUP), septoplasty with turbinate reduction, genioglossus advancement, and radiofrequency ablation of the palate have all been described in the literature.37-40 A study of LAUP in nine patients with UARS who underwent uvulopalatopharyngoplasty (n=2), multilevel pharyngeal surgery (n=1), or LAUP (n=6) reported improvements in subjective daytime sleepiness as measured with Epworth Sleepiness Scale scores.37 In the two patients for whom postoperative polysomnographic data was available, significant improvements in Pes nadir pressures were seen. But patients had several interventions and it is difficult to assess which one was successful. A study of 14 patients with UARS who underwent radiofrequency ablation of the palate also reported improvement in subjective sleepiness, with concurrent improvements in Pes nadir levels and reports of snoring.40 However, prior reviews of the available literature have noted that many of the studies evaluated small numbers of patients, consisted of uncontrolled case reports or series without clear characterization of the subjects enrolled, and had no consistent end points for an adequate evaluation of efficacy.39 Further investigation is required to determine the specific role for surgical intervention in these patients. Other authors have also reported successful treatment of UARS with use of oral appliances, although these studies suffer from the same limitations as the surgical literature.41 In children, orthodontic approaches, such as maxillary distraction or use of expanders, have also shown promising results.42

Conclusion

Although UARS has a symptomatology close to the one seen in patients with OSAS, there are distinct clinical differences between the two syndromes. In clinical studies, it is seen more in younger, slim subjects and in premenopausal women; it is more commonly associated with an increase in vagal tone during sleep than with sympathetic hyperactivity (as seen in association with apnea and hypopnea and oxygen desaturation).21 Can individuals with UARS become patients with OSAS? Guilleminault and colleagues1 suggested that weight increase (with development of a chest-bellow problem related to abdominal obesity) and the association of the supine position and sleep (leading to a restrictive impairment and secondary oxygen saturation drop and sympathetic hyperactivity) will lead to passage from one presentation to another with different complications; but more data are needed from additional systematic, longitudinal studies.1 UARS is underdiagnosed owing to unfamiliarity with the syndrome and the lack of polysomnographic criteria for either hypopneas or apneas that are associated with other types of sleep-disordered breathing. The advent of use of an esophageal catheter for esophageal pressure measurement (Pes) has allowed clinicians to more clearly identify patients with UARS. Although Pes measurement is the most sensitive method available to detect the abnormal respiratory events in UARS, it has not been used widely for several reasons, including lack of clinician experience and patient reports of discomfort. Usage of the nasal cannula pressure transducer allows recognition of flow limitation.43 But guidelines on how to tabulate the amount of flow limitation during total sleep time are lacking. Patients with UARS have significant impairment in their daytime functioning, with reports of sleepiness, fatigue, and sleep disruption. A follow-up study of these patients has shown that they often go untreated and experience progressive worsening of their symptoms. Among those patients who have been treated, typically with CPAP therapy, many have experienced symptomatic improvement. The current fund of knowledge regarding UARS has been growing, and we are beginning to understand the underlying pathophysiology.


 

References

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