A new approach in the diagnosis of upper airway resistance syndrome ( UARS ) : PAP method

Introduction: Upper airway resistance syndrome (UARS) is characterized by repeated number of arousals at night, and excessive daytime sleepiness or somnolence (EDS). It is often missed in classical polysomnographic diagnostic approaches and misdiagnosed as simple snoring or idiopathic hypersomnia, thereby is often left untreated. We propose that positive airway pressure (PAP), which has shown to be effective against UARS, can be used as a diagnostic tool as well. The study designed to test whether patients with high titration pressures can be diagnosed for UARS, and whether this pressure can be used as the treatment pressure in UARS.


INTRODUCTION
The upper airway resistance syndrome (UARS) has been described based on the hypothesis that snoring and repetitive occurrence of RERAs without oxygen desaturation might cause a significant disease with symptoms, altered quality of life and cardiovascular morbidity.The syndrome was first defined in pediatric patients in 1982 and in adult patients in 1993 by Guilleminault (1).Although the description of RERA, American Academy of Sleep Medicine (AASM) has not accepted UARS as a distinct disease among sleep braething disorders.AASM has concluded that the current clinical and pathophysiological data are not sufficient to specifying UARS as a distinct conditon but instead defined it as borderline of Obstructive Sleep apnea (OSA).The International Classification of Sleep Disorders II's (ICSD II) 2005 version is consistent with the AASM in the matter.It is still controversial whether UARS, with its strong relationship with cardiovascular complications, needs to be regarded as a distinct disease (1,2).With UARS various neuropsychiatric symptoms such as Bruxism, irritable bowel syndrome, insomnia, and somatic problems as well as excessive daytime sleepiness, and major cardiovascular problems are known to occur (3)(4)(5).
We believe that UARS is a different disease from OSA, as it triggers sympathetic nervous system activation without causing apnea/hypopnea and desaturation.We also believe that UARS should be recognized as a disease that need to be treated, because its results in fatigue and excessive daytime sleepiness (EDS) and, has major cardiovascular consequences.Although there exists globally accepted criteria that can help us in UARS diagnosis, many patients remain undiagnosed and this group can not taken under the essential treatment (Table 1).
Based on these ideas, we set out to investigate a new method that will be cost and time-effective in patients where classical PSG points to a possibe UARS.Detection of increase in upper respiratory tract resistance will confirm of the diagnosis and the need for treatment.
This study was planned with the idea that, using treatment-diagnostic method, positive airway pressure (PAP) can be useful in diagnosing the disease and could also be used to determine the treatment pressure in the same session.

PAP Titration
Auto-PAP titration was performed along with PSG to patients who met the aforementioned criteria by Res Med AutoSet T 1999 model.
Patients with average pressure over 4 cmH 2 O during titration were considered to have increased resistance of the upper respiratory tract.

Endpoint
In healthy individuals the upper respiratory tract pressure does not exceed 4 cmH 2 O. PAP titration values over this pressure is the best proof that there is an increase in resistance on the patient's upper respiratory tract.
Primary endpoint: On a patient that we demonstrate an upper airway resistance increase, if the OSA criteria are not met (AHI < 5 and no desaturation) and the patient experiences excessive daytime sleepiness, this patient can be diagnosed to have UARS (Table 1).
Secondary endpoint: It is widely accepted all over the world that diseases with major cardiovascular complications should be treated.UARS also causes this complication and we believe that this is the absolute indication for treatment.We know that nowadays the most effective treatment of upper airway pressure increase is PAP.The prerequisite for PAP therapy to patients is to determine the pressure they need and the methods we use for this purpose is the PAP titration.
After demonstrating increased resistance in the upper airway for the diagnosis of UARS by PAP titration we also learn positive pressure that the patient needs for therapy at the same time.So this means we can offer the patient the diagnosis and treatment options in the same session.
This method eliminated the need for invasive and untolerated methods like esophageal pressure measurement, which is used to make a definitive diagnosis of UARS.PAP method is more effective in terms of cost, more comfortable for the patient and less timeconsuming for both the patient and the physician.

Statistical Analysis
The data obtained in the study were evaluated using the SPSS 16.0 package program.Statistical analysis of the cases demographics, polysomnographic recording results and descriptive statistics were used in the evaluation of PAP titration results.Results were given as mean values accompanied by standard deviation.

RESULTS
Thirty patients included to the study according to the PSG results and history consideration who were diagnosed as UARS.Fourteen (46.7%) of the patients were male, and 16 (53.3%)were female.The mean age was 46.4 ± 9.9.While determining EDS by the Epworth Sleepiness Questionnaire all patients were over 10 points and mean score was 15 ± 3.9.The mean AHI was 2.3 ± 1.4, and mean RERA was 26.1 ± 4.9 (Table 2).
During PAP titration, the results were pathological and the mean pressure was 7.  3).

DISCUSSION
This study demonstrates that UARS diagnosis can be confirmed and PAP pressure needed for treatment can be determined in the same session.The gold standard method for the diagnosis of UARS is Esophageal Pressure Measurement.Decreased esophageal pressure (PES) is the earliest indication of respiratory arousals caused by increased upper airway resistance.However, this method is not being used by many labs because of the disruption of sleep quality, not being well tolerated by patients , and because it is an invasive procedure (4,5,7).Therefore, a more practical method for diagnosis is resorted to.Today, PSG is imperative to ensure the diagnosis of UARS.It is required to have AHI< 5, and RERA significantly high with no desaturation.In addition to these criteria, the presence of EDS leads to the diagnosis of UARS in the patients (1,4,8).All of the patients included in our study had AHI below 5 and RERA over 20.In all patients, EDS was confirmed by the Epworth Sleepiness Questionnaire.
UARS diagnosis is not easy due to the following reasons: Esophageal Pressure Measurement is an invasive method and is difficult to tolerate for the patients.There is no limit to RERA number to clarify the UARS diagnosis in PSG.Moreover, there are no objective methods available in practice in EDS.However, we know that increased upper airway resistance is a pathological event.
PSG results with no apnea/hypopnea or desaturation, but an increase in resistance in the upper respiratory tract directly lead us to the diagnosis of UARS.As we know, the pressure in the upper respiratory tract of a healthy person does not exceed 4 cm H 2 O.The most objective way to prove the upper airway resistance with non-invasive method is to perform a PAP titration.
In our country, like many parts of the world, the opinion to consider UARS as a separate disease is dominant (9).But the AASM and the ICSD-2, considers UARS as a preliminary step of OSA.In a study conducted by Guilleminault and colleagues, longterm follow-up results with a diagnosis of UARS patients who did not receive PAP therapy were published.According to this study, only 5 of 94 patients (5.3%) developed OSA.Rather than OSA, daytime sleepiness, fatigue, insomnia, difficulty concentrating, and depression has been found to be significantly increased in frequency among these patients.
In addition, the same patients showed significantly increased use of hypnotic, antidepressant and stimulant drugs (10).
The complications of OSA can be explained by apnea/hypopnea and desaturation.However, UARS shows none of these symptoms, and develops similar complications with OSA just by arousals.This suggests that treatment of UARS should be taken more seriously.
In cases with sleep disorders breathing, remarkable hypertension is observed due to increased upper airway resistance.In hypertensive patients the incidence of OSAS is 30-40%, and the incidence of non-apneic snoring is 30-70% (4.5).
In one of their studies Guilleminault and colleagues showed that the borderline hypertension has been shown by to be controlled with CPAP therapy in patients with UARS.In pediatric patients, UARS have been reported to cause complications like behavioral disorders, and school failure (4,7,10,11).
In our opinion, due to the excessive daytime sleepiness, major cardiovascular problems, and the adverse effects during childhood, patients with UARS should be treated.The goal of treatment is to improve symptoms and quality of life, to reduce the morbidity and mortality of the disease by overcoming the increased upper airway resistance.Generally applicable methods for the treatment of OSAS are used for UARS (4,5,13).
Nowadays PAP therapy is the most effective treatment to overcome the resistance of the upper airway.
With the use of PAP therapy, neuropsychiatric symptoms significantly improved and EDS has been shown to decrease.Even the demostration of an improvement in EDS is with PAP therapy is among the minor diagnostic criteria (1,4,13).
In one study, Guilleminault and colleagues observed that CPAP treatment or turbinectomy showed much better results than behavioral therapy alone in postmenopausal women with UARS who suffered from daytime fatigue and chronic insomnia (14).
For the patients to be treated with PAP, PAP titration is the first examination to be done.Pressure determined after PAP titration, is the threshold pressure necessary to keep the patient's upper respiratory tract open.We determined the accurate pressures necessary for our patients by PAP titration.
As already mentioned, we kept two things in mind when we performed PAP titration to our patients suspected to have UARS.First, if we observe pressure over 4 cmH 2 O during PAP titration, this proves the presence of patient's upper airway resistance.Second,
For diagnosis 3 major and 3 minor criteria must be met.UARS: Upper airway resistance syndrome, AHI: Apnea-hypopnea index, RERA: Respiratory event related arousal, EEG: Electroencephologram, CPAP: Continues positive airway pressure.participants Figure 1.The flow diagram of patients admitted to sleep laboratuary.

Table 3 .
Sleep effi ciency and sleep stages of patients