Defining occurrence & influence of alpha-delta sleep in CFS

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From: Fred Springfield

Via: CO-CURE

Defining the occurrence and influence

of alpha-delta sleep in chronic fatigue syndrome.

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Journal: Am J Med Sci. 2007 Feb;333(2):78-84.

Van Hoof E, De Becker P, Lapp C, Cluydts R, De Meirleir K.

From the Department of Human Physiology (evh, pdb, kdm) and the

Department of Psychology (evh, rc), Vrije Universiteit, Brussels,

Belgium; and from the Hunter-Hopkins Center, Charlotte, North

Carolina (cl).

NLM Citation: PMID: 17301585

BACKGROUND:

Patients with chronic fatigue syndrome (CFS) present a disordered

sleep pattern and frequently undergo polysomnography to exclude a

primary sleep disorder. Such studies have shown reduced sleep

efficiency, a reduction of deep sleep, prolonged sleep initiation, and

alpha-wave intrusion during deep sleep. Deregulation of the 2-5A

synthetase/RNase L antiviral pathway and a potential acquired

channelopathy are also found in a subset of CFS patients and could

lead to sleep disturbances. This article compiles a large sleep study

database on CFS patients and correlates these data with a limited

number of immune parameters as it has been thought that RNase L

could be associated with these sleep disturbances.

METHODS:

Forty-eight patients who fulfilled 1994 Centers for Disease Control

and Prevention criteria for CFS underwent extensive medical

evaluation, routine laboratory testing, and a structured psychiatric

interview. Subjects then completed a complaint checklist and a

two-night polysomnographic investigation. RNase L analysis was

performed by gel electrophoresis using a radiolabeled

2',5'-oligoadenylate trimer. Basic descriptive statistical parameters

were calculated.

RESULTS:

Patients experienced a prolonged sleep latency, showed a low sleep

efficiency index, and had a low percentage of slow wave sleep. The

present alpha-delta intrusion correlated with anxiety; no correlations

appeared, however, between alpha-delta sleep and immunologic

parameters, including RNase L.

CONCLUSIONS:

The main findings are

1) validation of sleep latency problems and other sleep disturbances

as already suggested by several authors;

2) alpha-delta intrusion seems associated with anxiety; and

3) elevated RNase L did not correlate with alpha-delta sleep.

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~jvr: as fair use I add the discussion section of this article

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Discussion

Sleep architecture variables demonstrated significantly different

sleep onset latency and sleep disturbances in CFS patients (Table

4). Because of the resemblance between the CFS patients used by

Fischler et al13 and Fossey et al15 and our CFS population, their

results may apply to our sample, although no healthy control group

was used. Similar results were already reported by several other

authors, such as Whelton et al10 and Stough and Withers.14 CFS

patients present less sleep continuity. Patients experience problems

falling asleep, represented by the large sleep latency. The low sleep

efficiency index and the high number of micro-awakenings objectify

the subjectively presented complaints of a distorted sleep pattern

and a nonrestorative sleep.5–7 The patients slept about 5.5 hours.

They spent almost 30% of the time awake in bed. Interestingly, a lot

of shifts between stages are apparent. Again, the results of the sleep

architecture underscore the distorted sleep pattern and an

unrefreshing sleep.

Alpha-delta intrusion is present although a wide range of the

percentage of this intrusion indicates its nonspecific nature. This

sleep anomaly is thought to be accompanied by indications of

vigilance during sleep and the subjective experience of unrefreshing

sleep. The latter seems not solely associated with alpha-delta

intrusion because no differences in feelings of fatigue and

unrefreshing sleep could be found between CFS patients with low or

high alpha-delta intrusion. Our results emphasize the nonspecific

nature of alpha-delta sleep in CFS patients, a suggestion made by

several authors.19–23 For instance, Manu and associates found no

correlation between alpha-delta sleep and CFS, fibromyalgia, major

depression, primary sleep disorders, or Lyme disease but did find

that alpha-delta sleep was more common among chronic fatigue

patients without major depressive disorders.23

Although the sample showed high RNase L, no differences were

apparent between patients with low and high alpha-delta intrusion.

Furthermore, no correlations appeared between alpha-delta sleep

and immunologic parameters, including RNase L. So far, it has been

thought that a potential acquired channelopathy, a consequence of

immune deregulation through RNase L, leads to sleep disturbances

including alpha-delta sleep.25,26 Our results suggests that RNase L

and the subsequent channelopathy are not associated with

alpha-delta intrusion. Moreover, none of the self-reported sleep

problems, nor the objective sleep parameters, are associated with

RNase L. This result questions at least a part of the suggested

hypothesis proposed by Englebienne and De Meirleir.25 The

suggested acquired channelopathy with loss of intracellular

potassium should lead to metabolic and intracellular abnormalities,

including central fatigue and sleep disturbances such as alpha-delta

intrusion. Our results do not support the inclusion of sleep

disturbances in- cluding alpha-delta intrusion in the list of potential

consequences of the suggested channelopathy.

The results the deregulation of the 2–5A synthetase/ RNase L

pathway are similar to those of previous studies.27,28 It is still

unclear, however, whether the 37 kDa RNase L ratio is

representative of the CFS population in general, and whether the 37

kDa RNase L ratio is characteristic of a particular stage in the

course of the illness or if it fluctuates over time (as is the case with

symptom severity in the majority of CFS patients). Recent research

suggest the ratio could be associated with (the severity) of the

experienced complaints and its associated clinical causes.25 For

instance, the deregulation of the 2-5A synthetase/RNase L pathway

appears to accompany different aspects of immune dysfunction in

CFS patients. A reduced number and activity (cytotoxicity) of

NK-cells have been reported in patients with CFS.29–31 In addition,

a negative correlation between the RNase L ratio and both the

number and percentage of NK-cells was observed in CFS patients.

In our study, no deviant NK-cells percentages were found. Moreover,

no correlations were found between the RNase L ratio and the

NK-cells.

To be a biological gradient, a correlation between the biological

parameter of interest (i.e., impairment of the RNase L pathway) and

the clinical severity of the disorder of interest (i.e., CFS) is required.

No significant correlations regarding self-reported complaints,

objective sleep parameters, and immune parameters were found in

this study. For interpreting a correlation analysis, however, one

should focus on the correlation coefficient rather than interpreting the

P-value. Correlation coefficients as low as 0.2, regardless of the

P-value, suggest no association is present. Although no significant

associations were found, some correlation coefficients suggested

possible relationships. The Bonferroni-corrections and the small

sample size could prevent any significant results. Further research

is necessary to clarify possible associations. Using our present

results, no significant findings appeared, casting into question the

biological gradient of the RNase L ratio regarding the NK-cells and

sleep disturbances.

Anxiety differed between low and high alphadelta sleep. People

suffering from high alpha-delta intrusion experience more anxiety.

Anxiety could be the result of the higher vigilance in slow wave sleep.

The major clinical importance of this study is that because of alpha

wave intrusion in phase 3 and 4 of the non-REM sleep, full benefit is

not taken from the recuperative function of slow wave sleep.

This study had several limitations. First, the study was done

retrospectively and therefore strong causal relations were difficult to

make. Second, a limited number of CFS patients were enrolled and

there was no healthy control group, although the results were similar

to those of Fischler et al13 and Fossey et al,15 who did include a

healthy control group. Therefore, more research is needed, not only

with a increased number of CFS patients that would give more

accurate results, but also with the same polysomnographic protocol

and adequate control subjects, including patients with

non-CFS-induced fatigue. The relatively small number of CFS

patients in this study was due to recent changes in

polysomnographic protocols; only 41 CFS patients were found to

have completed a similar 2-night polysomnographic protocol.

Moreover, 1-night polysomnographic protocols should be avoided

due to the first-night effect.32 In summary, one obvious limitation of

the present study is the lack of power due to a small sample size.

However, the well-documented expense related to laboratory sleep

research,33 as well as the difficulties regularly encountered with

subject attrition in such extensive, demanding, and lengthy

investigations make small sample size an unfortunate but common

consequence. Nevertheless, the comprehensive data collected

make an important contribution to CFS research and should form

the basis for future investigations.

Summarizing, the main findings of this study are as follows:

1) The existence of sleep latency problems and other sleep

disturbances are validated, as already suggested by several

authors.

2) Alpha-delta intrusion seems associated with anxiety.

3) An elevated RNase L-ratio did not correlate with alphadelta sleep.

4) The results from the correlation analysis questions RNase L as a

biological gradient. To our knowledge, this is the first study in which

immune parameters were correlated to polysomnographic variables

in CFS patients. More research is undoubtedly necessary to state

causal relationships, although some interesting suggestions have

been made.