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in Disorders of Excessive Daytime Sleepiness:
Role of Sleep Disturbance and Obesity
Excessive Daytime Sleepiness (EDS), the most common complaint at Sleep Disorder Centers, are most often associated with sleep apnea, narcolepsy, or idiopathic hypersomnia. Little is known about chemicals in the blood which could contribute to these symptoms. Yet of certain chemicals thought involved with sleep, called inflammatory cytokines, one (interleukin-1 or IL-1) has been shown to cause somnolence when administered to normal human subjects. A related chemical, IL-6, which has similar effects, is increased in patients with sleeping sickness (African trypanosomiasis). The current study explored whether IL-1-beta, IL-6, or another inflammatory cytokine called tumor necrosis factor-alpha (TNFalpha) might play a role in EDS associated with sleep disorders.
Subjects consisted of 12 patients with obstructive sleep apnea, 11 with narcolepsy, 8 with idiopathic hypersomnia, and 10 normal controls. To eliminate artefacts which might affect the cytokines, study criteria excluded patients over 55 years of age, patients on methylphenidate (Ritalin) or other stimulants, those on antiinflammatory medications within one week before the study, and those with any active infection or inflammatory disease such as arthritis.
All patients and controls were given standard all-night laboratory sleep studies; also, patients with narcolepsy and idiopathic hypersomnolence were studied for two naps after the all-night studies. Blood samples for measurement of cytokines were drawn in the morning after the sleep study.
Blood TNFalpha was elevated in both apneics and narcoleptics compared to controls. IL-6 was elevated only in sleep apneics. IL-1beta was not significantly different in any group.
Both TNFalpha and IL-6 were positively correlated with the presence of Excess Daytime Sleepiness to a significant degree. Also, the levels of IL-6 were correlated with the intensity of EDS in narcoleptics and the combined group of narcoleptics and idiopathic hypersomnolent patients.
TNFalpha levels were correlated with the degree of nighttime sleep disturbance and of hypoxia. IL-6 levels were correlated with the Body Mass Index, the degree of nighttime hypoxia, and the degree of nocturnal sleep disturbance.
TNFalpha and IL-6 appeared relevant to EDS in these sleep disorders because, first of all, they were elevated in patients with sleep apnea or narcolepsy (but not those with idiopathic hypersomnolence): second, they were correlated with the presence of EDS and IL-6 was correlated with its severity; third, both were correlated with degree of nighttime sleep disturbance and hypoxia.
The lack of significant elevations in idiopathic hypersomnolence or significant correlations within this group may have been due to the smaller number of patients in this group, or a lesser degree of EDS in these patients. The lack of significant elevations of or correlations with IL-1beta may have been due to insufficient sensitivity of the test for levels of this chemical.
The authors note that the levels of these cytokines follow a regular daily rhythm with peaks in the early morning hours (1-2 am), typically the time of slow wave sleep, whereas the blood drawing took place several hours later on awakening. The levels would be higher at the earlier time and might also be much higher in the central nervous system than in the blood.
The authors noted the strong correlation of Body Mass Index with IL-6 and the fact that IL-6 and TNFalpha were highest in the sleep apnea group, which had the highest BMIs. Plasma TNFalpha levels are also elevated in obese animals and humans without sleep apnea. Even without sleep apnea, the authors have found obesity to be associated with complaints of fatigue, EDS, and nighttime sleep disturbance. These symptoms may be mediated by cytokines, especially IL-6. There are also findings that sleep deprivation in humans raises levels of TNFalpha.
Could these cytokines represent “sleepiness” or “fatigue” hormones, elevated by obesity and/or sleep disruption, which mediate the effect of these conditions in causing Excessive Daytime Sleepiness? It is exciting to think of this possibility because it might lead to specific medications to antagonize or reduce these chemicals and thereby relieve these symptoms. On the other hand, this study seems still far from that point. For one thing, as the authors point out, their numbers of subjects are small. For another thing, a correlation is far from a cause (or an effect). Many other factors may exist that mediate such correlations, which may be quite remote from the actual cause-and-effect relationships.
In their efforts to exclude patients with inflammatory diseases which might raise cytokines, I wonder if the authors considered the possibility that obstructive sleep apnea may cause inflammation of the upper airway? This possibility is discussed in other articles summarized on this website (see Article #19 and Article #37).
The idea that obesity might be a cause of EDS separate from its role in causing and/or being caused by obstructive sleep apnea is an intriguing one. I will await with interest the publication of the authors’ results in that study. Especially I will be interested in how thoroughly they have eliminated the possibility of UARS among their group of non-apneic obese subjects. The other possibility that would need careful thought is that a person who is fatigued or hypersomnolent for any reason, or no known reason, could become obese as a result of reduced activity and/or the use of food in an effort to restore energy or combat depression resulting from their lack of energy. Depression, for that matter, is a physiological state which should be controlled for in any study of chemical imbalance in either sleep disordered or obese aubjects.
All of this is interesting, and useful insofar as it reinforces the conviction of many that the sleep disorders are fundamentally physical ailments, not to be unfairly confounded with character defects of sloth or gluttony, which I fear is still too often the case!
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