Upper Airway Resistance Syndrome Is a Distinct Syndrome

Christian Guilleminault and Susmita Chowdhuri

Stanford University Sleep Disorders Center, Stanford, California

	ARTICLE

TOP ARTICLE REFERENCES

Gastaut and coworkers described sleep-disordered breathing in polymorbid somnolent patients or "Pickwickians" (1). Subsequently, we characterized obstructive events during non-rapid eye movement (NREM) sleep in somnolent but nonobese subjects as obstructive sleep apnea syndrome (OSAS) (2). Further investigations in nonobese individuals revealed repetitive increased respiratory effort terminated by transient arousals, but without associated airway collapse, hypoventilation, or oxygen desaturation: the "upper airway resistance syndrome" (UARS) (3).

UARS is a distinct syndrome that occurs in a distinct population. There is a false assumption that it forms a continuum between primary snoring and OSAS. This is because investigations have not meticulously eliminated confounding factors such as android obesity and other comorbidities in the study populations. Any attempt to understand the differences between OSAS and UARS must be based on investigations in nonobese subjects, and must include sensitive measures of respiratory effort, i.e., esophageal manometry (4), as well as electroencephalogram (EEG) arousal.

In our series of 400 cases of UARS, 93 have "pure" UARS. These patients frequently complain of insomnia, sleep fragmentation, and fatigue (5, 6). Their mean age is 38 ± 14 yr; 56% are women, and 32% are of east Asian origin. Hence, their sex, age, and racial distribution are different from those with OSAS. The mean body mass index is  23.2 ± 2.8 kg/m², the mean respiratory disturbance index is 1.5, and oxygen saturation is  95%. Their craniofacial anatomy reveals a predominantly high and narrow hard palate, an abnormally small intermolar distance, an abnormal overjet  3 mm, and a thin soft palatal mucosa with a short uvula. In 88% of the subjects, there is a history of early extraction or absence of wisdom teeth (7). Their psychological profile shows a high anxiety score. Other clinical features are cold extremities, postural hypotension, history of fainting, and low blood pressure. In a subgroup of 15 subjects, between 20 and 30 yr of age, orthostasis is present by tilt testing, and is associated with a low mean systemic arterial blood pressure. Four breathing patterns are noted with repetitive transient arousals (8): (1) "Pes crescendo": progressively increasing esophageal pressure (Pes), terminated by reversal of the Pes to baseline; (2) increased Pes, without crescendo, terminated by a Pes reversal; (3) one or two breath increases in Pes preceding a Pes reversal; and (4) tachypnea with normal Pes, abruptly terminated by a normal breath. At the beginning of the sleep study, the average peak inspiratory effort during NREM sleep is low (mean Pes, 2.5 cm H₂O). Typically, the events are terminated at low negative peak inspiratory pressure (6 cm H₂O) (9).

In contrast, in OSAS, collapse of the upper airway typically occurs when the intrathoracic pressure falls to 20 to 30 cm H₂O (10, 11). The arousal threshold is at inspiratory pressures of 40 to 80 cm H₂O, thus indicating that the arousal threshold for increased inspiratory effort is elevated in OSAS (11, 12).

In UARS, the arousal threshold is lower. The recognition of the internal respiratory load is exquisitely sensitive, therefore allowing the patient to wake up in response to small increases in inspiratory effort. The sleep EEG in UARS shows an increase in alpha rhythm (13, 14). There is a relative increase in delta sleep, which persists in the later cycles of sleep. These patients may present with hypotension. The mechanism by which hypotension can occur in UARS has been outlined by Seals and colleagues (15).

In contrast, sleep in OSAS shows a predominance of stage 1 and 2 NREM sleep with a decrease in delta sleep. The absolute power of distribution of EEG bands during sleep shows a preponderance of theta rhythm (13). In addition, there is overactivation of the autonomic nervous system with demonstrable increases in muscle sympathetic nerve activity and increased blood pressure both during sleep and waking hours (13, 16). Clearly, UARS and OSAS markedly differ from each other in terms of their clinical presentation, sleep EEG, and autonomic nervous system responses.

The argument that UARS eventually evolves into OSAS is too simplistic. This does not account for the occurrence in our group of overweight individuals of UARS that does not evolve into OSAS, over a period of years (5). Berry and Gleason (11) hypothesized that polyneuropathy of the upper airway nerve endings induced by snoring (Friberg and coworkers [17, 18]) may lead to impaired upper airway mechanoreceptor function and hence to OSAS. However, this cannot explain the presence of UARS in patients who do not snore. Others have postulated that UARS may progress to OSAS secondary to chronic sleep fragmentation. Why would other conditions associated with chronic sleep fragmentation (such as periodic limb movement disorder) not lead to the development of obstructive sleep-disordered breathing?

We believe that distinct functional arousal reflex pathways originating from peripheral mechanoreceptors exist in these two groups. The subjects with UARS have intact, sensitive receptor function while the subjects with OSAS have primary receptor dysfunction. In other words, subjects with blunted mechanoreceptor responses would develop OSAS, while those with intact or hypersensitive responses would develop UARS. This would explain our group of untreated patients whose UARS did not evolve into OSAS over time. Central nervous system responses to respiratory effort, mediated by these mechanoreceptors, have been investigated by studying respiratory related evoked potentials (19) during sleep. Preliminary data from patients with OSAS indicate that these are blunted compared with normal controls (I. M. Colrain, personal communication, 1999).

In summary, the data suggest that a fundamental difference exists between patients with UARS and patients with OSAS. This difference is determined by the different mechanoreceptor function in the two groups, which is, presumably, genetically predetermined and environmentally altered. This might explain why subjects with a hypersensitive response pattern will develop UARS, whereas subjects with a dysfunctional response pattern, modified by factors such as chronic respiratory allergies, postpubertal tongue enlargement, etc., will directly develop OSAS. In addition, it is interesting to note that the autonomic nervous system responses are also polar opposites in the two groups (9, 17). We believe that two different "brain" responses best explain the two different syndromes. If appropriate physiologic investigations had focused more on nonobese subjects, these differences would have been observed much earlier.

	References

TOP ARTICLE REFERENCES

1. Gastaut, H., C. A. Tassinari, and B. Duron. 1965. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res. 2: 167-186 .

2. Guilleminault, C., F. Eldridge, and W. C. Dement. 1972. Insomnia, narcolepsy and sleep apnea. Bull. Pathophysiol. Respir 8: 1127-1138 .

3. Guilleminault, C., R. Stoohs, A. Clerk, M. Cetel, and P. Maistros. 1993. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest 104: 781-787 [Abstract/Free Full Text].

4. Flemale, A., C. Guilleminault, and J. P. Diercky. 1998. Comparison of central venous, esophageal and mouth occlusion pressure with water-filled catheter for estimation of pleural pressure changes in healthy adults. Eur. Respir. J 1: 51-57 .

5. Guilleminault, C., R. Stoohs, Y. D. Kim, R. Chervin, J. Black, and A. Clerk. 1995. Upper airway sleep disordered breathing in women. Arch. Intern. Med 122: 493-501 .

6. Guilleminault, C., J. E. Black, L. Palombini, and M. Ohayon. 2000. A clinical investigation of obstructive sleep apnea syndrome and upper airway resistance syndrome patients. Sleep Med 1: 1-6 . [Medline]

7. Kushida, C. A., B. Efron, and C. Guilleminault. 1997. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann. Intern. Med 127: 581-587 .

8. Sleep Disorders Atlas Task Force. 1992. EEG arousals: scoring rules and examplesa preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 15: 174-184 .

9. Guilleminault, C. Postural hypotension and UARS (abstract). J. Sleep Res. (In press)

10. Issa, F. G., and C. E. Sullivan. 1983. Arousal and breathing responses to airway occlusion in healthy sleeping adult. J. Appl. Physiol 55: 1113-1119 [Abstract/Free Full Text].

11. Berry, R. B., and K. Gleeson. 1997. Respiratory arousal from sleep mechanisms and significance. Sleep 20: 654-675 [Medline].

12. Kimoff, R. J., T. H. Cheong, A. E. Opha, M. Charbonneau, R. D. Levy, M. G. Cosio, and S. B. Gottfried. 1994. Mechanisms of apnea termination in obstructive sleep apnea: role of chemoreceptor and mechanoreceptor stimuli. Am. J. Respir. Crit. Care Med. 149: 707-714 [Abstract].

13. Guilleminault, C., Y. D. Kim, M. Horita, M. Tsutum, and R. Pelayo. 1999. Power spectral EEG findings in patients with obstructive sleep apnea and upper airway resistance syndromes. Electroencephalogr. Clin. Neurol 50(Suppl.): 109-112 .

14. Guilleminault, C., J. Black, and O. Carillo. 1997. EEG arousal and upper airway resistance (abstract). Electroencephalogr. Clin. Neurol 1: 11 .

15. Seals, D. R., N. O. Suwarno, M. J. Joyner, C. Iber, J. G. Copeland, and J.A. Dempsey. 1993. Respiratory modulation of muscle sympathetic nerve activity in intact and lung denervated humans. Circ. Res 77: 440-454 .

16. Carlson, J. T., J. Hedner, M. Elam, and et al. 1993. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea syndrome. Chest 103: 1763-1768 [Abstract/Free Full Text].

17. Friberg, D., T. Ansved, K. Borg, B. Carlsson-Nordlander, H. Larsson, and E. Svanborg. 1998. Histological indication of a progressive snorers disease in the upper airway muscle. Am. J. Respir. Crit. Care Med 157: 586-593 [Abstract/Free Full Text].

18. Friberg, D., B. Gazelius, T. Hokfelt, and B. Norlander. 1997. Abnormal afferent nerve endings in soft palate mucosa of sleep apneics and habitual snorers. Regul. Pept 71: 29-36 [Medline].

19. Wheatley, J. R., and D. P. White. 1993. Influence of NREM sleep on respiratory-related cortical evoked potentials in normal humans. J. Appl. Physiol 74: 1803-1810 [Abstract/Free Full Text].

20. Webster, K. E., and I. M. Colrain. 1998. Multi-channel EEG analysis of respiratory related evoked potential during wake and NREM sleep. J. Appl. Physiol 85: 1727-1755 [Abstract/Free Full Text].

21. Colrain, I. M., K. E. Webster, and G. Hirst. 1999. The N550 component of the evoked K-complexes: a modality nonspecific response? J. Sleep Res 8: 273-280 .