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Upper airway resistance syndrome: A long-term outcome study
JOURNAL OF PSYCHIATRIC RESEARCH
Journal of Psychiatric Research 40 (2006) 273–279
www.elsevier.com/locate/jpsychires
Upper airway resistance syndrome: A long-term outcome study Christian Guilleminault a,*, Ceyda Kirisoglu a, Dalva Poyares a, Luciana Palombini a, Damien Leger a, Mehran Farid-Moayer a, Maurice M. Ohayon b b
a Stanford Sleep Disorders Clinic, 401 Quarry Road, Ste. 3301, Stanford, CA 94305, United States Stanford Sleep Epidemiology Research Center, School of Medicine, Stanford University, CA, United States
Received 8 December 2004; received in revised form 17 March 2005; accepted 23 March 2005
Abstract This prospective study aimed to assess symptomatic evolution of patients diagnosed with Upper Airway Resistance Syndrome (UARS) four and half years after the initial UARS diagnosis. For this purpose, 138 UARS patients were contacted by mail between 43 and 69 months after the initial evaluation; 105 responded to the letter and 94 patients accepted to undergo new clinical and polysomnographic evaluations. Initial and followup polysomnographic recordings were scored using the same criteria. Results: Of the 94 patients who completed the follow-up examination, none of them were using nasal CPAP. It was related to refusal by insurance providers to provide equipment based on initial apnea–hypopnea index (AHI) in 90/94 subjects. Percentage of patients with sleep related-complaints significantly increased over the four and half year period: daytime fatigue, insomnia and depressive mood increased by 12 to 20 times. Reports of sleep maintenance sleep onset insomnia and depressive mood was significantly increased. Hypnotic, antidepressant and stimulant prescription increased from initial to follow-up visit (from 11.7% to 61.7%; from 3.2% to 25.5% and from 0% to 9.6%, respectively) with antidepressant given as much for sleep disturbance as mood disorder. The polysomnography results at follow-up showed that 5 subjects had AHI compatible with Obstructive Sleep Apnea Syndrome (OSAS) but overall, respiratory disturbance index had no significant change. Total sleep time was significantly reduced compared to initial visit. Conclusions: Many UARS patients remained untreated following initial evaluation. Worsening of symptoms of insomnia, fatigue and depressive mood were seen with absence of treatment of UARS. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Upper Airway Resistance Syndrome; Prospective survey; Sleep maintenance insomnia; Sleep onset insomnia; Hypnotics; Antidepressants; Stimulants
1. Introduction Upper Airway Resistance Syndrome (UARS) (Guilleminault et al., 1993, 2000) is associated with abnormal respiratory effort, nasal airflow limitation, absence of obstructive sleep apnea, minimal pulse oxygen fluctuation with oxygen saturation (SaO2) equal or *
Corresponding author. Tel.: +1 650 723 6601; fax: +1 650 725 8910. E-mail address: [email protected] (C. Guilleminault). 0022-3956/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2005.03.007
greater than 92%, and frequent nocturnal arousals or reflex brainstem activation (Morruzi, 1963). Patients with UARS frequently complain of daytime tiredness and fatigue. It has been emphasized that these patients present more as patients with functional somatic syndromes than those presenting with Obstructive Sleep Apnea Syndrome (OSAS) (Gold et al., 2003; Guilleminault et al., 2001a,b,c). There have been questions about the usefulness of identifying this syndrome independently from the OSAS, and questions on its long-term evolution (Douglas, 2000). The treatment of UARS is
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not well clarified: nasal continuous positive airway pressure (nCPAP) was used in the initial report (Guilleminault et al., 1993) to demonstrate response to short term upper airway widening during sleep, but long term prescription has had variable success (Guilleminault et al., 2002). Finally not only the incidence of the syndrome is unknown but also is its natural history. To improve our knowledge on several of these points, we designed a prospective study on a retrospective cohort. We questioned the outcome of the diagnostic evaluation and the treatment recommendation performed on subjects labeled UARS patients at least 4 years prior the start of the prospective study. We questioned if their illness had progressed, if their symptoms had changed and if the prescribed treatment (nCPAP) had been helpful. Due to health insurance policies and contractual agreements with health policy payers, regulations of the medical center, and views of the medical center by the surrounding local medical community, our sleep disorders clinic functioned for many years as referral clinic performing diagnosis and treatment recommendations, with a one time patient contact, and no further interaction if not initiated by the referring primary care physician. Due to these specific conditions we built-up our prospective protocol.
2. Materials and methods
(3) 18 channels nocturnal polysomnography with usage of esophageal pressure transducer. A diagnosis of UARS was made based on the association of complaints, clinical symptoms and polygraphic findings. The scoring criteria for polysomnography were kept constant over time. The definition for presence of an OSAS was based on an apnea–hypopnea index (AHI) P 5 events/hour, with definition of an apnea as an event with cessation of airflow for at least 10 s terminated with a drop of SaO2 > 3% or/and an EEG arousal P3 s. Hypopnea was defined as 30% or more reduction in nasal airflow channel compared to prior normal breathing for duration of 10 s or more, terminated with a drop of SaO2 P 3% and/or an EEG arousal P3 s. The definition of an UARS was based on an AHI (number of apnea and hypopnea per hour of sleep) <5, and oxygen saturation >92% throughout the night (Guilleminault et al., 2001a,b,c; Bao and Guilleminault, 2004; AASM, 1999), other breathing abnormalities were seen based on the analysis of the nasal cannula pressure transducer system and of the esophageal pressure (Pes) curve (the scoring criteria are described below) (Bao and Guilleminault, 2004; AASM, 1999; Guilleminault et al., 1995; ASDA, 1992; Black et al., 2000). All patients underwent a second night of nocturnal polysomnography for determination of appropriate pressure necessary for control of the breathing disorder using nasal CPAP, subsequently they received a prescription for equipment, and were referred back to their primary care physician.
2.1. Subjects For this investigation, we attempted to contact all patients (n = 138) who were diagnosed with UARS at Stanford Sleep Disorders Clinic between 1995 and 1998. 2.2. Procedures 2.2.1. Initial evaluation Diagnosis of UARS was based on: (1) Complaints of daytime fatigue, tiredness, or sleepiness, report of nocturnal sleep disruption with variable difficulty to go back to sleep or presence of symptoms associated with sleep disordered breathing (Basiri and Guilleminault, 2000). (2) Clinical evaluation: Patients completed validated questionnaires (Sleep Disorders Questionnaire (SDQ) (Douglass et al., 1994), Epworth Sleepiness Scale (ESS) (Johns, 1991)), Hamilton depression scale, had a clinical evaluation that included determination of body mass index (BMI), neck circumference, cranio-facial features with systematic face and profile photos and usage of published clinical scales (Friedman et al., 1999; Mallampati et al., 1985).
2.2.2. Follow-up A mean of 4 and 1/2 years later, all 138 patients were contacted by mail using the last address available in the health system directory. Up to three successive letters were mailed out. The patients were asked to call us. The letter explained the goal of the phone call and they were asked to come back for a research follow-up. Patients who called were explained again about the goals of the study, content of a consent form was read to them, and they gave an informed consent over the telephone. Additionally, they were offered to come back for a re-evaluation that included a new polysomnogram, and to discuss further treatment options. For subjects who declined clinical follow-up, a 5-min questionnaire and the ESS (Johns, 1991) were administered on the phone. The brief questionnaire investigates changes in initial symptoms and complaints, major changes in health status, and response to the nasal CPAP prescription. Patients who accepted to come to clinic signed informed consent, filled a new set of questionnaires including SDQ (Douglass et al., 1994), ESS (Johns, 1991), Hamilton depression scale, and a 15-day sleep diary. Additionally, they were evaluated for their current health status, medications, and underwent a physi-
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cal exam with measurements of body mass index (BMI), neck circumference, and re-evaluation of oro-pharyngeal anatomy (Friedman et al., 1999; Mallampati et al., 1985). To eliminate the inter-scorer variability, the same clinician performed the clinical evaluations. 2.3. Polysomnography The same montage was used in initial evaluation and follow-up recording. Each time patients underwent a one-night polysomnography; the following variables were monitored: electroencephalogram (EEG) (C3/A2, C4/A1, Fz/A1–A2, O1/A2), electrooculogram (EOG) of both eyes, chin and leg electromyograms (EMGs), electrocardiogram (ECG) with modified V2 lead, and respiration by using nasal cannula pressure transducer, mouth thermistor, thoracic and abdominal impedance belts, esophageal pressure manometer (Pes), neck microphone, and pulse oximetry (SaO2). Recordings were performed on the same computerized polygraphic sleep systems (Sandmanä, Kanata, Ont., Canada). Polysomnographic recordings from the initial and follow-up evaluations were all scored by an individual blind to diagnostic and date of recording. The same international criteria were used for recording (AASM, 1999; ASDA, 1992; Rechtschaffen and Kales, 1968). All records were re-scored following the same criteria including the initial records of subjects that did not come back from a second follow-up recording. Sleep and wake was scored following the international criteria (Rechtschaffen and Kales, 1968) and short arousals were determined following the American Sleep Disorders Association recommendations (ASDA, 1992). The criteria to score breathing during sleep were set before any scoring and followed the international criteria (AASM, 1999): Apnea and hypopnea were defined as indicated above (AASM, 1999). As indicated above, patients who had an AHI < 5, and oxygen saturation >92% throughout the night were considered with UARS and apnea and hypopnea were defined using international definition. Other respiratory variables were scored to affirm pathology in UARS patients. They were: (a) presence of abnormal nasal cannula curve for a duration of at least 10 s with disappearance of the normal round shape of a breath and presence of a ‘‘flattening’’ of the curve as previously defined by Hosselet et al. (1998), with a reduction of in nasal airflow between 3% and 30% compared to prior normal breaths; (b) presence of a change in the Pes curve lasting at least 4 breaths; these changes, as previously defined (Guilleminault et al., 2001a,b,c), could be of 2 types: either with a more negative peak end inspiratory pressure with each successive breath called a Pes crescendo, or with a more negative peak end inspiratory Pes reached in one or 2 breaths but with maintenance of an elevated but leveled peakend inspiratory value, called a ‘‘continuous sustained
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effort’’ (Guilleminault et al., 2001a,b,c). These two indicators of increase respiratory effort may or may not have been associated with a ‘‘flattening’’ of the nasal cannula. The Pes events terminated with an EEG arousal, and following the American Academy of Sleep Medicine recommendations (AASM, 1999), were called ‘‘Respiratory-Event-Related-Arousal’’ (RERA), or terminated only with an abrupt return to a lesser respiratory effort with sudden decrease in negative peak end inspiratory Pes called a ‘‘Pes reversal’’(Guilleminault et al., 1995, 2001a,b,c) but without an EEG arousal 3 s or longer or a SaO2 drop of 3% or more. These abnormal breathing events were tabulated together with the apnea and hypopnea; and a ‘‘respiratory disturbance index’’ (RDI) was calculated (number of abnormal respiratory events/hour of sleep). 2.4. Statistical analysis Kruskal–Wallis analysis of variance test with post hoc test with Bonferroni correction was used to compare results on initial and follow-up evaluations. Mann Whitney U-test was used to compare two groups and normally distributed pair t-test was used for repeated measures. Percentages were compared using v2 statistics. P-value was set at <0.05. All statistical analysis was carried out using SPSS statistical package, version 11.5.
3. Results 3.1. Initial evaluation About 138 subjects including 88 women were identified from the computerized database. Men were significantly younger than women. (P-value < 0.05) (Table 1) No other significant differences were found between men and women. Symptoms at entry are presented in Tables 2A,2B(A and B). All patients complained of disrupted nocturnal sleep. Five percent of all subjects had complaints of sleep onset insomnia. There were 7 patients with a Hamilton D scale with a score between 15 and 18 (4 of them were in the follow-up study). All subjects had a AHI < 5 events/hour, but presented a higher RDI. All subjects had had a second polysomnography for nasal CPAP titration at time of initial visit and the prescribed nasal CPAP pressure ranged between 5 and 8 cm H2O. 3.2. Follow-up One hundred and five patients (76% of retrospective group) called in response to the mailings. They included 72 women and 33 men (respectively 87.5% and 66% of initial group). Eleven of them (7 men) declined to have
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Table 1 Demographics of the patients on the first and current clinical evaluation Total group
Initial visit n = 138 Female (n = 88)
Male (n = 50)
Age (yrs) BMI (kg m 2) AHI (events/h) RDI (events/h) ESS
30.8 ± 4.1 23.8 ± 1.3 2.3 ± 0.5 8.4 ± 3.2 9.1 ± 1.2
26.3 ± 3.2 24.1 ± 2.1 2.4 ± 0.6 9.5 ± 3.1 8.8 ± 1.9
(18–43) (19–26) (0.3–4) (5.1–12.8) (6-12)
(22–31) (19–27) (0.4–4) (5.2–14.2) (5–12)
Prospective cohort
Initial visit n = 94
Follow-up visit n = 94
Female (n = 68)
Male (n = 26)
Female (n = 68)
Male (n = 26)
Age (yrs) BMI (kg m 2) AHI (events/h) RDI (events/h) ESS
30.0 ± 4.8 23.4 ± 1.9 2.2 ± 0.6 8.6 ± 3.4 9.3 ± 1.3
26.3 ± 3.5 23.7 ± 2.3 2.4 ± 0.6 9.5 ± 3.4 8.6 ± 1.6
35.1 ± 4.8 23.6 ± 1.8 2.4 ± 1.1 8.3 ± 3.8 9.4 ± 1.4
30.4 ± 3.5 24.0 ± 3.0 2.5 ± 1.2 9.9 ± 4.1 9.1 ± 2.0
(19–26) (0.3–4) (5.3–12.8) (7–12)
(19–27) (0.4–4) (5.5–14.2) (5–11)
(19–26.5) (0.4–4) (5.1–13) (6–12)
(19–28.5) (0.4–9) (5.5–15) (6–12)
Values are depicted as mean, standard deviation, and range. BMI: body mass index, AHI: Apnea hypopnea index, RDI: Respiratory disturbance index, ESS: Epworth sleepiness scale. Top table presents group at first visit (n = 138), bottom table presents the prospective study group (n = 94) with results when first seen and during current study. There is no significant difference between the total group and the prospective group at first visit for any of the considered variables. Table 2A Clinical complaints and symptoms at initial visit and follow-up visit Complaints/symptoms
Initial visit (n = 138) n (%)
Follow-up visit with assumption X (n = 138) n (%)
P < v2
(A) Subjects at initial visit Snoring Daytime fatigue Disrupted nocturnal sleep Sleep maintenance insomnia Difficulty concentrating Daytime irritability Morning headaches or heaviness of the head Sleep onset insomnia Daytime sleepiness Depressed mood
101 109 138 47 79 51 22 7 11 8
90 94 94 80 78 69 36 50 20 47
0.02 (–) 0.02 (–) 0.02 0.0001 0.04 Ns Ns 0.0001 Ns 0.0001
(73.2) (79) (100) (34) (57) (37) (16) (5) (8) (5.8)
(65.2) (68) (68) (58) (56.5) (50) (26) (36) (15) (34)
If we assume that all subjects that did not responded to the offer of a new evaluation had appropriate treatment (an assumption – called here assumption X – that we already know is inaccurate from the 11 subjects phone interview) and were controlled for their sleep disordered breathing, we can see that the untreated subjects would still significantly positively impact the total results and a larger number of subjects would complained of clinical symptoms except for snoring and daytime fatigue.
follow-up investigation at the clinic. Out of those 11 patients, 2 subgroups could be identified: (1) 3 women that had received nasal CPAP as prescribed, had seen clear improvement of their initial symptoms, were having regular contact with their physicians and medical equipment providers and were non-complainer; (2) 8 patients who still had regular nocturnal snoring, complaints similar as at entry (n = 4) or reported worsening of nocturnal sleep disruption (n = 4). ESS scores were not significantly changes from initial visit. All these 8 patients were currently untreated: phone short interviews revealed that 5 patients never had their CPAP prescription filled, 2 tried CPAP for one month but due to insurance issues had their CPAP discontinue, and one
patient stopped his CPAP after 6 months of intermittent usage and nasal intolerance of the treatment. Ninety-four patients (68% of retrospective group), (68 women) agreed to come back for a new evaluation and new polysomnography and are called the ‘‘prospective cohort’’. The follow-up investigation occurred between 43 and 69 months after initial evaluation (mean of 54.2 months). 3.2.1. Outcome of nasal CPAP prescription None of the subjects were treated with nasal CPAP. About 90 out of 94 had had their request for nasal CPAP treatment rejected by health insurance at time of initial request, and in 4 cases after first month of deliverance of equipment by medical equipment suppli-
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Table 2B Complaints/symptoms
Initial visit (n = 94) n (%)
Follow-up visit (n = 94) n (%)
(B) Complaints of patients with UARS in the prospective study at initial visit and at follow-up Snoring 75 (79.8) 90 (95.7) Daytime fatigue 78 (83) 94 (100) Disrupted nocturnal sleep 94(100) 94 (100) Sleep maintenance insomnia 30 (32) 80 (85) Difficulty concentrating 47 (50) 78 (83) Daytime irritability 37 (39) 69 (63) Morning headaches or heaviness of the head 18 (19) 36 (38) Sleep onset insomnia 5 (5.3) 50 (53.2) Daytime sleepiness 9 (9.5) 20 (21.3) Depressed mood 7 (7.4) 47 (50)
OR (95%CI)
P< v2
5.7 19.1 1.0 12.2 4.9 4.3 2.6 20.2 2.6 12.4
0.001 0.0001 Ns 0.0001 0.0001 0.0001 0.004 0.0001 0.03 0.0001
(1.9–17.5) (2.5–>40) (6.0–24.9) (2.5–9.6) (2.3–7.9) (1.4–5.1) (7.5–54.3) (1.1–6.0) (5.2–29.7)
When subjects of the follow-up were investigated, a much larger number of subjects complained during the current study that at time of initial visit. The most important changes were on the number of subjects reporting sleep maintenance insomnia, sleep onset insomnia and depressed mood. Subjects complained of disturbed nocturnal sleep at first visit but did not mention ‘‘insomnia’’, but their views of their problem lead them to emphasize much more the sleep disturbance.
ers. The rational for the rejection of the nasal CPAP prescription was always the same: ‘‘patients did not meet criteria for prescription of nasal CPAP’’ set by insurance company experts that also referred to criteria set by professional societies. General practitioner made no appeal. No referral back to sleep clinic was made based on low AHI and belief by practitioners that sleep disordered breathing had been ruled-out due to low AHI. 3.2.2. Clinical complaints All subjects presented sleep related complaints at the follow-up interview. None of the subjects had spontaneous improvement. All mentioned persistence of sleep related problems. Tables 2A,2B(A and B) present complaints at initial and follow-up visits. As seen, frequency of complaints had significantly increased during the elapsed time between the 2 evaluations. The highest increases were seen for fatigue, insomnia, and scores at the Hamilton depression scale with 47 subjects with a score of 15 or above, (with 5 subjects with scores between 19 and 22). 3.2.3. Medication intake As disrupted nocturnal sleep, poor sleep and sleep onset insomnia were frequent complaints, patients were symptomatically treated and a significant increase in hypnotic medication prescription was seen at current visit: At time of first visit 19/138 (14%) patients were taking hypnotic medication for their nocturnal sleep disturbances. These 19 included 11 subjects that were in the prospective cohort (11.7%). At the follow-up evaluation 58 subjects (61.7%) were using hypnotic medications more than twice per week prescribe by private practitioner (P = 0.0001; v2 statistics). At initial visit 6/138 (4%) subjects (3 of them – 3.2% – in the follow-up cohort) had had prescription of specific serotonin re-uptake inhibitors (SSRI). At the follow-up evaluation, 24 (25.5%) received a SSRI, Trazodone or
Venlafaxine. Mostly the medication was prescribed by a general practitioner for insomnia more than depressive mood; 8 subjects only had been referred to a psychiatrist. In summary, at the time of first visit 15/138 subjects (16%) had received hypnotic or antidepressant medications due to poor sleep mostly and sometime associated depressive mood. At the follow-up evaluation, 82/94 (87.2%) had sought medical help, and were prescribed medications in relation with their insomnia and in some cases due to the depressive mood. Stimulant medication: No patient received stimulant at initial visit, but 9/94 subjects (9.6%) were receiving modafinil (200 mg/AM) due to daytime complaint; 6/9 used both a medication at bedtime due to poor sleep and modafinil in the morning due to impaired alertness and difficulty at work. Clinical interviews and system evaluations showed no significant change in blood pressure, cardio-vascular or neurological status. 3.3. Polysomnography The overall AHI and RDI at follow-up, when the 94 subjects were tabulated, were not significantly different from those measured at the initial visit (see Table 1). Individual results indicated however, that 5 out of 94 subjects (3 men) were now diagnosed with OSAS. They had an AHI P 5 events/hour (mean 7 ± 2.3, range 5– 11). The changes were associated with increase in weight, particularly in the subject with the highest increase in AHI (AHI = 11) had a 8 kg weight gain. However, the overall BMI did not significantly change for the total group (Table 1). Lowest SaO2 was very moderately affected in these 5 subjects with OSAS, as the overall lowest reading seen in association with one event was 88%. Total recording time was kept constant between the 2 sleep studies, with 8.00 h of dark time. The mean total sleep time (TST) was 355 ± 31 min at
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the initial evaluation but it was only 302 ± 28 min (P = 0.001) at the follow-up evaluation, with longer time awake from light out supporting claims of insomnia. Light out was based on patient preference and was not significantly change from first visit. Since respiratory events are calculated based on sleep time, this reduction in TST did not impacted calculation. In summary, the 94 untreated UARS patients, for the large majority (n = 89) did not evolve toward OSAS in 4 and half years; the very few that did, increase their body mass index. But the complaints involved a much larger group of subjects and were much more numerous (Table 2BB). Practitioners responded to these complaints with symptomatic treatments that had limited success. Even if we assume that all subjects that did not respond to our letters and/or to the offer to have a new investigation were without UARS (assumption called ‘‘assumption X’’, and assumption that we already know as flawed due to response to short questionnaire for 11 subjects), there would still be a significantly higher percentage of subjects with complaints and with more complaints at current study (see Table 2AA). The increase in complaint is associated with a shorter TST and more sleep disruption after light out, at current recording.
4. Discussion This is the first study that examines the natural evolution of patients diagnosed with UARS. The results clearly showed that sleep and daytime symptoms in untreated UARS increased over time and there was no case of spontaneous remission of symptoms. More specifically, the likelihood of having daytime fatigue, insomnia or depressive mood had a 12 to 20 times increase over a 4-year period. One of the direct consequences was the increase in hypnotic and antidepressant prescription: 11.7% and 3.2% and at initial visit compared with 61.7% and 25.5% at the follow-up. The first conclusion is that despite claims that UARS is recognized, integrated for some in the OSAS (Douglas, 2000), and treated; there was a clear refusal to support treatment by medical insurances in the late 90s based on definitions provided by professional medical societies, and secondary negation of presence of the syndrome in the medical community. The difference in clinical presentation and polygraphic findings between UARS and the better known OSAS includes complaints usually associated with functional somatic syndromes and AHI < 5 events/hour. The lack of education on UARS in the medical community, and the controversies related to its position within sleep disordered breathing, lead practitioners to accept the decisions from medical insurance plans, and lead them to treat patients symptomatically and without challenging the refusal of more
specific treatment. One clear motivation for many subjects to participate to the study was assurance to address the initially diagnosed health problem. Our study also shows that UARS patients with weight (and BMI) increase may evolve toward a defined OSAS, but this concerned a limited number of patients; the vast majority of patients did not increase their weight significantly and were still UARS four and half years later. On the other hand, the number of patients with clinical complaints related to their poor sleep and its daytime consequences greatly increased over time despite absence of progression toward OSAS, and absence of polysomnographic evidence of worsening of sleep disordered breathing indices. One of the interesting outcomes was that the worsening of nocturnal sleep disturbance not only involved a greater number of complainers but was also associated with a greater sleep disruption as demonstrated by polysomnography. This worsening was associated with a greater amount of wakefulness after light out; and the absence of significant increase in the number of abnormal breathing events between initial and follow-up polysomnography may be related to this increase in amount of awake time during the night. Interestingly, subjects developed sleep onset insomnia and not only maintenance insomnia. These findings have to be placed together and may give some insights on the development of chronic insomnia: We still have little knowledge on the factors contributing to the development of chronic insomnia. Many chronic illnesses may lead to insomnia complaint, but the specific role of a sleep disorder as a predisposing factor for development of sleep onset insomnia is not well understood. In a previous study on post-menopausal women with chronic insomnia, we have shown that sleep disordered breathing is not only common, but also that treating the underlying breathing disorder can improve some of the complaints (Guilleminault et al., 2002). Moreover, this improvement was observed using nasal CPAP that is not the most effective treatment for UARS. Our study showed that untreated UARS is associated with chronic sleep onset and sleep maintenance insomnia and depressive mood. And the chronic complaint led to chronic prescription of hypnotics and antidepressant medications in about 60% of the prospective cohort, without addressing the underlying cause of the sleep disruption. Another outcome is that UARS patients present very commonly with functional somatic complaints (Gold et al., 2003) including insomnia, headache, myalagia, daytime fatigue. These symptoms do not orient immediately toward a SDB in general practice, as UARS is not necessarily on the differential diagnosis list of these related complaints. If subjects are referred to sleep specialists it is important not only to perform appropriate investigation but also to follow the patient and provide the referring physician with help in securing the appro-
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priate treatment for the patient, as non specialists may decide, in absence of clear support and help from the specialist, to treat symptomatically using hypnotics, antidepressant, and stimulant drugs, without valid treatment response. Overall the outcomes found with this study are disappointing: Despite efforts to emphasize the existence of the UAR syndrome and to emphasize need to treat the sleep disordered breathing very few subjects were in fact treated at the beginning of the new millennium; and despite polysomnography, failure to convince the referring practitioner at the initial visit did not bring the patient back to specialist. But absence of treatment lead to development of more complaints that lead to an inadequate treatment response; the UARS and its non-recognition is a challenge for the field of Sleep Medicine.
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www.elsevier.com/locate/jpsychires
Upper airway resistance syndrome: A long-term outcome study Christian Guilleminault a,*, Ceyda Kirisoglu a, Dalva Poyares a, Luciana Palombini a, Damien Leger a, Mehran Farid-Moayer a, Maurice M. Ohayon b b
a Stanford Sleep Disorders Clinic, 401 Quarry Road, Ste. 3301, Stanford, CA 94305, United States Stanford Sleep Epidemiology Research Center, School of Medicine, Stanford University, CA, United States
Received 8 December 2004; received in revised form 17 March 2005; accepted 23 March 2005
Abstract This prospective study aimed to assess symptomatic evolution of patients diagnosed with Upper Airway Resistance Syndrome (UARS) four and half years after the initial UARS diagnosis. For this purpose, 138 UARS patients were contacted by mail between 43 and 69 months after the initial evaluation; 105 responded to the letter and 94 patients accepted to undergo new clinical and polysomnographic evaluations. Initial and followup polysomnographic recordings were scored using the same criteria. Results: Of the 94 patients who completed the follow-up examination, none of them were using nasal CPAP. It was related to refusal by insurance providers to provide equipment based on initial apnea–hypopnea index (AHI) in 90/94 subjects. Percentage of patients with sleep related-complaints significantly increased over the four and half year period: daytime fatigue, insomnia and depressive mood increased by 12 to 20 times. Reports of sleep maintenance sleep onset insomnia and depressive mood was significantly increased. Hypnotic, antidepressant and stimulant prescription increased from initial to follow-up visit (from 11.7% to 61.7%; from 3.2% to 25.5% and from 0% to 9.6%, respectively) with antidepressant given as much for sleep disturbance as mood disorder. The polysomnography results at follow-up showed that 5 subjects had AHI compatible with Obstructive Sleep Apnea Syndrome (OSAS) but overall, respiratory disturbance index had no significant change. Total sleep time was significantly reduced compared to initial visit. Conclusions: Many UARS patients remained untreated following initial evaluation. Worsening of symptoms of insomnia, fatigue and depressive mood were seen with absence of treatment of UARS. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Upper Airway Resistance Syndrome; Prospective survey; Sleep maintenance insomnia; Sleep onset insomnia; Hypnotics; Antidepressants; Stimulants
1. Introduction Upper Airway Resistance Syndrome (UARS) (Guilleminault et al., 1993, 2000) is associated with abnormal respiratory effort, nasal airflow limitation, absence of obstructive sleep apnea, minimal pulse oxygen fluctuation with oxygen saturation (SaO2) equal or *
Corresponding author. Tel.: +1 650 723 6601; fax: +1 650 725 8910. E-mail address: [email protected] (C. Guilleminault). 0022-3956/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2005.03.007
greater than 92%, and frequent nocturnal arousals or reflex brainstem activation (Morruzi, 1963). Patients with UARS frequently complain of daytime tiredness and fatigue. It has been emphasized that these patients present more as patients with functional somatic syndromes than those presenting with Obstructive Sleep Apnea Syndrome (OSAS) (Gold et al., 2003; Guilleminault et al., 2001a,b,c). There have been questions about the usefulness of identifying this syndrome independently from the OSAS, and questions on its long-term evolution (Douglas, 2000). The treatment of UARS is
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not well clarified: nasal continuous positive airway pressure (nCPAP) was used in the initial report (Guilleminault et al., 1993) to demonstrate response to short term upper airway widening during sleep, but long term prescription has had variable success (Guilleminault et al., 2002). Finally not only the incidence of the syndrome is unknown but also is its natural history. To improve our knowledge on several of these points, we designed a prospective study on a retrospective cohort. We questioned the outcome of the diagnostic evaluation and the treatment recommendation performed on subjects labeled UARS patients at least 4 years prior the start of the prospective study. We questioned if their illness had progressed, if their symptoms had changed and if the prescribed treatment (nCPAP) had been helpful. Due to health insurance policies and contractual agreements with health policy payers, regulations of the medical center, and views of the medical center by the surrounding local medical community, our sleep disorders clinic functioned for many years as referral clinic performing diagnosis and treatment recommendations, with a one time patient contact, and no further interaction if not initiated by the referring primary care physician. Due to these specific conditions we built-up our prospective protocol.
2. Materials and methods
(3) 18 channels nocturnal polysomnography with usage of esophageal pressure transducer. A diagnosis of UARS was made based on the association of complaints, clinical symptoms and polygraphic findings. The scoring criteria for polysomnography were kept constant over time. The definition for presence of an OSAS was based on an apnea–hypopnea index (AHI) P 5 events/hour, with definition of an apnea as an event with cessation of airflow for at least 10 s terminated with a drop of SaO2 > 3% or/and an EEG arousal P3 s. Hypopnea was defined as 30% or more reduction in nasal airflow channel compared to prior normal breathing for duration of 10 s or more, terminated with a drop of SaO2 P 3% and/or an EEG arousal P3 s. The definition of an UARS was based on an AHI (number of apnea and hypopnea per hour of sleep) <5, and oxygen saturation >92% throughout the night (Guilleminault et al., 2001a,b,c; Bao and Guilleminault, 2004; AASM, 1999), other breathing abnormalities were seen based on the analysis of the nasal cannula pressure transducer system and of the esophageal pressure (Pes) curve (the scoring criteria are described below) (Bao and Guilleminault, 2004; AASM, 1999; Guilleminault et al., 1995; ASDA, 1992; Black et al., 2000). All patients underwent a second night of nocturnal polysomnography for determination of appropriate pressure necessary for control of the breathing disorder using nasal CPAP, subsequently they received a prescription for equipment, and were referred back to their primary care physician.
2.1. Subjects For this investigation, we attempted to contact all patients (n = 138) who were diagnosed with UARS at Stanford Sleep Disorders Clinic between 1995 and 1998. 2.2. Procedures 2.2.1. Initial evaluation Diagnosis of UARS was based on: (1) Complaints of daytime fatigue, tiredness, or sleepiness, report of nocturnal sleep disruption with variable difficulty to go back to sleep or presence of symptoms associated with sleep disordered breathing (Basiri and Guilleminault, 2000). (2) Clinical evaluation: Patients completed validated questionnaires (Sleep Disorders Questionnaire (SDQ) (Douglass et al., 1994), Epworth Sleepiness Scale (ESS) (Johns, 1991)), Hamilton depression scale, had a clinical evaluation that included determination of body mass index (BMI), neck circumference, cranio-facial features with systematic face and profile photos and usage of published clinical scales (Friedman et al., 1999; Mallampati et al., 1985).
2.2.2. Follow-up A mean of 4 and 1/2 years later, all 138 patients were contacted by mail using the last address available in the health system directory. Up to three successive letters were mailed out. The patients were asked to call us. The letter explained the goal of the phone call and they were asked to come back for a research follow-up. Patients who called were explained again about the goals of the study, content of a consent form was read to them, and they gave an informed consent over the telephone. Additionally, they were offered to come back for a re-evaluation that included a new polysomnogram, and to discuss further treatment options. For subjects who declined clinical follow-up, a 5-min questionnaire and the ESS (Johns, 1991) were administered on the phone. The brief questionnaire investigates changes in initial symptoms and complaints, major changes in health status, and response to the nasal CPAP prescription. Patients who accepted to come to clinic signed informed consent, filled a new set of questionnaires including SDQ (Douglass et al., 1994), ESS (Johns, 1991), Hamilton depression scale, and a 15-day sleep diary. Additionally, they were evaluated for their current health status, medications, and underwent a physi-
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cal exam with measurements of body mass index (BMI), neck circumference, and re-evaluation of oro-pharyngeal anatomy (Friedman et al., 1999; Mallampati et al., 1985). To eliminate the inter-scorer variability, the same clinician performed the clinical evaluations. 2.3. Polysomnography The same montage was used in initial evaluation and follow-up recording. Each time patients underwent a one-night polysomnography; the following variables were monitored: electroencephalogram (EEG) (C3/A2, C4/A1, Fz/A1–A2, O1/A2), electrooculogram (EOG) of both eyes, chin and leg electromyograms (EMGs), electrocardiogram (ECG) with modified V2 lead, and respiration by using nasal cannula pressure transducer, mouth thermistor, thoracic and abdominal impedance belts, esophageal pressure manometer (Pes), neck microphone, and pulse oximetry (SaO2). Recordings were performed on the same computerized polygraphic sleep systems (Sandmanä, Kanata, Ont., Canada). Polysomnographic recordings from the initial and follow-up evaluations were all scored by an individual blind to diagnostic and date of recording. The same international criteria were used for recording (AASM, 1999; ASDA, 1992; Rechtschaffen and Kales, 1968). All records were re-scored following the same criteria including the initial records of subjects that did not come back from a second follow-up recording. Sleep and wake was scored following the international criteria (Rechtschaffen and Kales, 1968) and short arousals were determined following the American Sleep Disorders Association recommendations (ASDA, 1992). The criteria to score breathing during sleep were set before any scoring and followed the international criteria (AASM, 1999): Apnea and hypopnea were defined as indicated above (AASM, 1999). As indicated above, patients who had an AHI < 5, and oxygen saturation >92% throughout the night were considered with UARS and apnea and hypopnea were defined using international definition. Other respiratory variables were scored to affirm pathology in UARS patients. They were: (a) presence of abnormal nasal cannula curve for a duration of at least 10 s with disappearance of the normal round shape of a breath and presence of a ‘‘flattening’’ of the curve as previously defined by Hosselet et al. (1998), with a reduction of in nasal airflow between 3% and 30% compared to prior normal breaths; (b) presence of a change in the Pes curve lasting at least 4 breaths; these changes, as previously defined (Guilleminault et al., 2001a,b,c), could be of 2 types: either with a more negative peak end inspiratory pressure with each successive breath called a Pes crescendo, or with a more negative peak end inspiratory Pes reached in one or 2 breaths but with maintenance of an elevated but leveled peakend inspiratory value, called a ‘‘continuous sustained
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effort’’ (Guilleminault et al., 2001a,b,c). These two indicators of increase respiratory effort may or may not have been associated with a ‘‘flattening’’ of the nasal cannula. The Pes events terminated with an EEG arousal, and following the American Academy of Sleep Medicine recommendations (AASM, 1999), were called ‘‘Respiratory-Event-Related-Arousal’’ (RERA), or terminated only with an abrupt return to a lesser respiratory effort with sudden decrease in negative peak end inspiratory Pes called a ‘‘Pes reversal’’(Guilleminault et al., 1995, 2001a,b,c) but without an EEG arousal 3 s or longer or a SaO2 drop of 3% or more. These abnormal breathing events were tabulated together with the apnea and hypopnea; and a ‘‘respiratory disturbance index’’ (RDI) was calculated (number of abnormal respiratory events/hour of sleep). 2.4. Statistical analysis Kruskal–Wallis analysis of variance test with post hoc test with Bonferroni correction was used to compare results on initial and follow-up evaluations. Mann Whitney U-test was used to compare two groups and normally distributed pair t-test was used for repeated measures. Percentages were compared using v2 statistics. P-value was set at <0.05. All statistical analysis was carried out using SPSS statistical package, version 11.5.
3. Results 3.1. Initial evaluation About 138 subjects including 88 women were identified from the computerized database. Men were significantly younger than women. (P-value < 0.05) (Table 1) No other significant differences were found between men and women. Symptoms at entry are presented in Tables 2A,2B(A and B). All patients complained of disrupted nocturnal sleep. Five percent of all subjects had complaints of sleep onset insomnia. There were 7 patients with a Hamilton D scale with a score between 15 and 18 (4 of them were in the follow-up study). All subjects had a AHI < 5 events/hour, but presented a higher RDI. All subjects had had a second polysomnography for nasal CPAP titration at time of initial visit and the prescribed nasal CPAP pressure ranged between 5 and 8 cm H2O. 3.2. Follow-up One hundred and five patients (76% of retrospective group) called in response to the mailings. They included 72 women and 33 men (respectively 87.5% and 66% of initial group). Eleven of them (7 men) declined to have
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Table 1 Demographics of the patients on the first and current clinical evaluation Total group
Initial visit n = 138 Female (n = 88)
Male (n = 50)
Age (yrs) BMI (kg m 2) AHI (events/h) RDI (events/h) ESS
30.8 ± 4.1 23.8 ± 1.3 2.3 ± 0.5 8.4 ± 3.2 9.1 ± 1.2
26.3 ± 3.2 24.1 ± 2.1 2.4 ± 0.6 9.5 ± 3.1 8.8 ± 1.9
(18–43) (19–26) (0.3–4) (5.1–12.8) (6-12)
(22–31) (19–27) (0.4–4) (5.2–14.2) (5–12)
Prospective cohort
Initial visit n = 94
Follow-up visit n = 94
Female (n = 68)
Male (n = 26)
Female (n = 68)
Male (n = 26)
Age (yrs) BMI (kg m 2) AHI (events/h) RDI (events/h) ESS
30.0 ± 4.8 23.4 ± 1.9 2.2 ± 0.6 8.6 ± 3.4 9.3 ± 1.3
26.3 ± 3.5 23.7 ± 2.3 2.4 ± 0.6 9.5 ± 3.4 8.6 ± 1.6
35.1 ± 4.8 23.6 ± 1.8 2.4 ± 1.1 8.3 ± 3.8 9.4 ± 1.4
30.4 ± 3.5 24.0 ± 3.0 2.5 ± 1.2 9.9 ± 4.1 9.1 ± 2.0
(19–26) (0.3–4) (5.3–12.8) (7–12)
(19–27) (0.4–4) (5.5–14.2) (5–11)
(19–26.5) (0.4–4) (5.1–13) (6–12)
(19–28.5) (0.4–9) (5.5–15) (6–12)
Values are depicted as mean, standard deviation, and range. BMI: body mass index, AHI: Apnea hypopnea index, RDI: Respiratory disturbance index, ESS: Epworth sleepiness scale. Top table presents group at first visit (n = 138), bottom table presents the prospective study group (n = 94) with results when first seen and during current study. There is no significant difference between the total group and the prospective group at first visit for any of the considered variables. Table 2A Clinical complaints and symptoms at initial visit and follow-up visit Complaints/symptoms
Initial visit (n = 138) n (%)
Follow-up visit with assumption X (n = 138) n (%)
P < v2
(A) Subjects at initial visit Snoring Daytime fatigue Disrupted nocturnal sleep Sleep maintenance insomnia Difficulty concentrating Daytime irritability Morning headaches or heaviness of the head Sleep onset insomnia Daytime sleepiness Depressed mood
101 109 138 47 79 51 22 7 11 8
90 94 94 80 78 69 36 50 20 47
0.02 (–) 0.02 (–) 0.02 0.0001 0.04 Ns Ns 0.0001 Ns 0.0001
(73.2) (79) (100) (34) (57) (37) (16) (5) (8) (5.8)
(65.2) (68) (68) (58) (56.5) (50) (26) (36) (15) (34)
If we assume that all subjects that did not responded to the offer of a new evaluation had appropriate treatment (an assumption – called here assumption X – that we already know is inaccurate from the 11 subjects phone interview) and were controlled for their sleep disordered breathing, we can see that the untreated subjects would still significantly positively impact the total results and a larger number of subjects would complained of clinical symptoms except for snoring and daytime fatigue.
follow-up investigation at the clinic. Out of those 11 patients, 2 subgroups could be identified: (1) 3 women that had received nasal CPAP as prescribed, had seen clear improvement of their initial symptoms, were having regular contact with their physicians and medical equipment providers and were non-complainer; (2) 8 patients who still had regular nocturnal snoring, complaints similar as at entry (n = 4) or reported worsening of nocturnal sleep disruption (n = 4). ESS scores were not significantly changes from initial visit. All these 8 patients were currently untreated: phone short interviews revealed that 5 patients never had their CPAP prescription filled, 2 tried CPAP for one month but due to insurance issues had their CPAP discontinue, and one
patient stopped his CPAP after 6 months of intermittent usage and nasal intolerance of the treatment. Ninety-four patients (68% of retrospective group), (68 women) agreed to come back for a new evaluation and new polysomnography and are called the ‘‘prospective cohort’’. The follow-up investigation occurred between 43 and 69 months after initial evaluation (mean of 54.2 months). 3.2.1. Outcome of nasal CPAP prescription None of the subjects were treated with nasal CPAP. About 90 out of 94 had had their request for nasal CPAP treatment rejected by health insurance at time of initial request, and in 4 cases after first month of deliverance of equipment by medical equipment suppli-
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Table 2B Complaints/symptoms
Initial visit (n = 94) n (%)
Follow-up visit (n = 94) n (%)
(B) Complaints of patients with UARS in the prospective study at initial visit and at follow-up Snoring 75 (79.8) 90 (95.7) Daytime fatigue 78 (83) 94 (100) Disrupted nocturnal sleep 94(100) 94 (100) Sleep maintenance insomnia 30 (32) 80 (85) Difficulty concentrating 47 (50) 78 (83) Daytime irritability 37 (39) 69 (63) Morning headaches or heaviness of the head 18 (19) 36 (38) Sleep onset insomnia 5 (5.3) 50 (53.2) Daytime sleepiness 9 (9.5) 20 (21.3) Depressed mood 7 (7.4) 47 (50)
OR (95%CI)
P< v2
5.7 19.1 1.0 12.2 4.9 4.3 2.6 20.2 2.6 12.4
0.001 0.0001 Ns 0.0001 0.0001 0.0001 0.004 0.0001 0.03 0.0001
(1.9–17.5) (2.5–>40) (6.0–24.9) (2.5–9.6) (2.3–7.9) (1.4–5.1) (7.5–54.3) (1.1–6.0) (5.2–29.7)
When subjects of the follow-up were investigated, a much larger number of subjects complained during the current study that at time of initial visit. The most important changes were on the number of subjects reporting sleep maintenance insomnia, sleep onset insomnia and depressed mood. Subjects complained of disturbed nocturnal sleep at first visit but did not mention ‘‘insomnia’’, but their views of their problem lead them to emphasize much more the sleep disturbance.
ers. The rational for the rejection of the nasal CPAP prescription was always the same: ‘‘patients did not meet criteria for prescription of nasal CPAP’’ set by insurance company experts that also referred to criteria set by professional societies. General practitioner made no appeal. No referral back to sleep clinic was made based on low AHI and belief by practitioners that sleep disordered breathing had been ruled-out due to low AHI. 3.2.2. Clinical complaints All subjects presented sleep related complaints at the follow-up interview. None of the subjects had spontaneous improvement. All mentioned persistence of sleep related problems. Tables 2A,2B(A and B) present complaints at initial and follow-up visits. As seen, frequency of complaints had significantly increased during the elapsed time between the 2 evaluations. The highest increases were seen for fatigue, insomnia, and scores at the Hamilton depression scale with 47 subjects with a score of 15 or above, (with 5 subjects with scores between 19 and 22). 3.2.3. Medication intake As disrupted nocturnal sleep, poor sleep and sleep onset insomnia were frequent complaints, patients were symptomatically treated and a significant increase in hypnotic medication prescription was seen at current visit: At time of first visit 19/138 (14%) patients were taking hypnotic medication for their nocturnal sleep disturbances. These 19 included 11 subjects that were in the prospective cohort (11.7%). At the follow-up evaluation 58 subjects (61.7%) were using hypnotic medications more than twice per week prescribe by private practitioner (P = 0.0001; v2 statistics). At initial visit 6/138 (4%) subjects (3 of them – 3.2% – in the follow-up cohort) had had prescription of specific serotonin re-uptake inhibitors (SSRI). At the follow-up evaluation, 24 (25.5%) received a SSRI, Trazodone or
Venlafaxine. Mostly the medication was prescribed by a general practitioner for insomnia more than depressive mood; 8 subjects only had been referred to a psychiatrist. In summary, at the time of first visit 15/138 subjects (16%) had received hypnotic or antidepressant medications due to poor sleep mostly and sometime associated depressive mood. At the follow-up evaluation, 82/94 (87.2%) had sought medical help, and were prescribed medications in relation with their insomnia and in some cases due to the depressive mood. Stimulant medication: No patient received stimulant at initial visit, but 9/94 subjects (9.6%) were receiving modafinil (200 mg/AM) due to daytime complaint; 6/9 used both a medication at bedtime due to poor sleep and modafinil in the morning due to impaired alertness and difficulty at work. Clinical interviews and system evaluations showed no significant change in blood pressure, cardio-vascular or neurological status. 3.3. Polysomnography The overall AHI and RDI at follow-up, when the 94 subjects were tabulated, were not significantly different from those measured at the initial visit (see Table 1). Individual results indicated however, that 5 out of 94 subjects (3 men) were now diagnosed with OSAS. They had an AHI P 5 events/hour (mean 7 ± 2.3, range 5– 11). The changes were associated with increase in weight, particularly in the subject with the highest increase in AHI (AHI = 11) had a 8 kg weight gain. However, the overall BMI did not significantly change for the total group (Table 1). Lowest SaO2 was very moderately affected in these 5 subjects with OSAS, as the overall lowest reading seen in association with one event was 88%. Total recording time was kept constant between the 2 sleep studies, with 8.00 h of dark time. The mean total sleep time (TST) was 355 ± 31 min at
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the initial evaluation but it was only 302 ± 28 min (P = 0.001) at the follow-up evaluation, with longer time awake from light out supporting claims of insomnia. Light out was based on patient preference and was not significantly change from first visit. Since respiratory events are calculated based on sleep time, this reduction in TST did not impacted calculation. In summary, the 94 untreated UARS patients, for the large majority (n = 89) did not evolve toward OSAS in 4 and half years; the very few that did, increase their body mass index. But the complaints involved a much larger group of subjects and were much more numerous (Table 2BB). Practitioners responded to these complaints with symptomatic treatments that had limited success. Even if we assume that all subjects that did not respond to our letters and/or to the offer to have a new investigation were without UARS (assumption called ‘‘assumption X’’, and assumption that we already know as flawed due to response to short questionnaire for 11 subjects), there would still be a significantly higher percentage of subjects with complaints and with more complaints at current study (see Table 2AA). The increase in complaint is associated with a shorter TST and more sleep disruption after light out, at current recording.
4. Discussion This is the first study that examines the natural evolution of patients diagnosed with UARS. The results clearly showed that sleep and daytime symptoms in untreated UARS increased over time and there was no case of spontaneous remission of symptoms. More specifically, the likelihood of having daytime fatigue, insomnia or depressive mood had a 12 to 20 times increase over a 4-year period. One of the direct consequences was the increase in hypnotic and antidepressant prescription: 11.7% and 3.2% and at initial visit compared with 61.7% and 25.5% at the follow-up. The first conclusion is that despite claims that UARS is recognized, integrated for some in the OSAS (Douglas, 2000), and treated; there was a clear refusal to support treatment by medical insurances in the late 90s based on definitions provided by professional medical societies, and secondary negation of presence of the syndrome in the medical community. The difference in clinical presentation and polygraphic findings between UARS and the better known OSAS includes complaints usually associated with functional somatic syndromes and AHI < 5 events/hour. The lack of education on UARS in the medical community, and the controversies related to its position within sleep disordered breathing, lead practitioners to accept the decisions from medical insurance plans, and lead them to treat patients symptomatically and without challenging the refusal of more
specific treatment. One clear motivation for many subjects to participate to the study was assurance to address the initially diagnosed health problem. Our study also shows that UARS patients with weight (and BMI) increase may evolve toward a defined OSAS, but this concerned a limited number of patients; the vast majority of patients did not increase their weight significantly and were still UARS four and half years later. On the other hand, the number of patients with clinical complaints related to their poor sleep and its daytime consequences greatly increased over time despite absence of progression toward OSAS, and absence of polysomnographic evidence of worsening of sleep disordered breathing indices. One of the interesting outcomes was that the worsening of nocturnal sleep disturbance not only involved a greater number of complainers but was also associated with a greater sleep disruption as demonstrated by polysomnography. This worsening was associated with a greater amount of wakefulness after light out; and the absence of significant increase in the number of abnormal breathing events between initial and follow-up polysomnography may be related to this increase in amount of awake time during the night. Interestingly, subjects developed sleep onset insomnia and not only maintenance insomnia. These findings have to be placed together and may give some insights on the development of chronic insomnia: We still have little knowledge on the factors contributing to the development of chronic insomnia. Many chronic illnesses may lead to insomnia complaint, but the specific role of a sleep disorder as a predisposing factor for development of sleep onset insomnia is not well understood. In a previous study on post-menopausal women with chronic insomnia, we have shown that sleep disordered breathing is not only common, but also that treating the underlying breathing disorder can improve some of the complaints (Guilleminault et al., 2002). Moreover, this improvement was observed using nasal CPAP that is not the most effective treatment for UARS. Our study showed that untreated UARS is associated with chronic sleep onset and sleep maintenance insomnia and depressive mood. And the chronic complaint led to chronic prescription of hypnotics and antidepressant medications in about 60% of the prospective cohort, without addressing the underlying cause of the sleep disruption. Another outcome is that UARS patients present very commonly with functional somatic complaints (Gold et al., 2003) including insomnia, headache, myalagia, daytime fatigue. These symptoms do not orient immediately toward a SDB in general practice, as UARS is not necessarily on the differential diagnosis list of these related complaints. If subjects are referred to sleep specialists it is important not only to perform appropriate investigation but also to follow the patient and provide the referring physician with help in securing the appro-
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priate treatment for the patient, as non specialists may decide, in absence of clear support and help from the specialist, to treat symptomatically using hypnotics, antidepressant, and stimulant drugs, without valid treatment response. Overall the outcomes found with this study are disappointing: Despite efforts to emphasize the existence of the UAR syndrome and to emphasize need to treat the sleep disordered breathing very few subjects were in fact treated at the beginning of the new millennium; and despite polysomnography, failure to convince the referring practitioner at the initial visit did not bring the patient back to specialist. But absence of treatment lead to development of more complaints that lead to an inadequate treatment response; the UARS and its non-recognition is a challenge for the field of Sleep Medicine.
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