On Treatment but Still Sleepy

Cause and Management of Residual Sleepiness in Obstructive Sleep Apnea

Sandrine H. Launois; Renaud Tamisier; Patrick Lévy; Jean-Louis Pépin

Disclosures

Curr Opin Pulm Med. 2013;19(6):601-608. 

In This Article

Mechanism of Residual Sleepiness

Experimental studies in mice have shown that intermittent hypoxia, possibly through cell injury and apoptosis after activation of inflammatory and oxidative pathways, causes permanent brain damage in regions implicated in wake and sleep regulation.[39,40] These lesions are associated with persistent sleepiness after the animals are returned to a normoxic environment.[39] In OSA patients, irreversible nocturnal hypoxia-induced injury could take place in wakefulness promoting brain regions. Indeed, some studies have shown an association between daytime sleepiness and the severity of nocturnal oxyhemoglobin desaturation.[41] Thus, in some patients, irreversible damage induced by chronic nocturnal intermittent hypoxia could account for persistent sleepiness and cognitive dysfunction despite normalization of nocturnal breathing with CPAP. However, in studies focused on residual sleepiness, nocturnal hypoxia was not predictive of persistent sleepiness on CPAP.[17,26,28–30] Residual sleepiness patients are younger (less exposure time to OSA) and suffer from less severe OSA (less hypoxia) than patients who respond to CPAP. It is, therefore, unlikely that irreversible hypoxic brain lesions alone account for the persistence of sleepiness.

After exclusion of other causes of sleepiness, only a small proportion of patients, approximately 10%, remain sleepy on CPAP. Vulnerability to sleep deprivation or sleep disturbances is a trait-like characteristic[42] and could account for the inconsistent effect of CPAP on sleepiness in OSA patients. Identifying a subgroup of OSA patients at risk for residual sleepiness at the time of diagnosis would allow closer monitoring and earlier management of residual symptoms. Future studies examining CPAP response in OSA patients should evaluate whether a genetic biomarker may be able to predict 'CPAP-resistant syndrome'. The human leukocyte antigen (HLA) allele DQB1*0602 is significantly associated with narcolepsy, but also predicts interindividual differences in sleep, sleepiness, fatigue and response to chronic sleep deprivation in healthy adults.[42] Yet this promising genetic marker has proven an unlucky candidate in residual sleepiness patients as its prevalence is slightly lower in the residual sleepiness compared with the nonsleepy OSA group, 15 vs. 25%, and not different from healthy controls.[26]

A provocative and so far not formally tested hypothesis is that patients with residual sleepiness may belong to 'an extreme group of complainers'.[26] The fact that residual sleepiness patients also complain of fatigue, CPAP side-effects and poor quality of life could support this 'theory'.

Finally, one could argue that residual sleepiness simply reflects a prevalent complaint in the general population.[43,44] In a group of over 550 unselected OSA patients treated by CPAP, the prevalence of EDS was not significantly different from that in a group of community-based controls, leading the authors to reject the concept of 'post-CPAP sleepiness'.[45] However, the existence of EDS in the general population or in an unselected OSA population may actually be related to masked depression, short sleep duration and poor sleep hygiene, which all need to be excluded before a positive diagnosis of residual sleepiness is considered. In addition, the existence of associated symptoms that persist in spite of proper treatment (the 'CPAP-resistant syndrome') argues against a simple trait-like phenomenon.

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