Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study

Abstract:

BACKGROUND: The etiology and pathophysiology of chronic fatigue syndrome (CFS) remain inchoate. Attempts to elucidate the pathophysiology must consider sleep physiology, as unrefreshing sleep is the most commonly reported of the 8 case-defining symptoms of CFS. Although published studies have consistently reported inefficient sleep and documented a variable occurrence of previously undiagnosed primary sleep disorders, they have not identified characteristic disturbances in sleep architecture or a distinctive pattern of polysomnographic abnormalities associated with CFS.

METHODS: This study recruited CFS cases and non-fatigued controls from a population based study of CFS in Wichita, Kansas. Participants spent two nights in the research unit of a local hospital and underwent overnight polysomnographic and daytime multiple sleep latency testing in order to characterize sleep architecture.

RESULTS: Approximately 18% of persons with CFS and 7% of asymptomatic controls were diagnosed with severe primary sleep disorders and were excluded from further analysis. These rates were not significantly different. Persons with CFS had a significantly higher mean frequency of obstructive apnea per hour (p = .003); however, the difference was not clinically meaningful. Other characteristics of sleep architecture did not differ between persons with CFS and controls.

CONCLUSION: Although disordered breathing during sleep may be associated with CFS, this study generally did not provide evidence that altered sleep architecture is a critical factor in CFS. Future studies should further scrutinize the relationship between subjective sleep quality relative to objective polysomnographic measures.

 

Source: Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study. BMC Neurol. 2006 Nov 16;6:41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1660569/ (Full article)

 

beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome

Abstract:

BACKGROUND: Due to the occurrence of sleep disturbances and fatigue in chronic fatigue syndrome (CFS), an investigation was performed to examine if there is an abnormal excretion of gamma-aminobutyric acid (GABA) and/or its structural analogue beta-alanine in the urine from CFS patients. Both GABA and beta-alanine are inhibitory neurotransmitters in the mammalian central nervous system.

METHODS: The 24 h urine excretion of GABA and beta-alanine was determined by isotope dilution gas chromatography mass spectrometry in 33 CFS patients and 43 healthy controls. The degree of symptoms in both patients and controls was measured by grading of three typical CFS symptoms using a Visual Analogue Scale.

RESULTS: Men had a significantly higher excretion of both beta-alanine and GABA than women. Comparing CFS patients with healthy controls showed no significant difference in excretion of neither beta-alanine nor GABA. No correlation was found between the excretion of beta-alanine or GABA and any of the three characteristic CFS symptoms measured. However, two female and two male CFS patients excreted considerably higher amounts of beta-alanine in their 24 h urine samples than control subjects.

CONCLUSIONS: Increased excretion of beta-alanine was found in a subgroup of CFS patients, indicating that there may be a link between CFS and beta-alanine in some CFS patients.

 

Source: Hannestad U, Theodorsson E, Evengård B. beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome. Clin Chim Acta. 2007 Feb;376(1-2):23-9. Epub 2006 Jul 14. https://www.ncbi.nlm.nih.gov/pubmed/16934791

 

Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion

Abstract:

The effect of melatonin, a chronobiotic drug, was explored in 29 patients with chronic fatigue syndrome (CFS) and Dim Light Melatonin onset (DLMO) later than 21.30 hours, reflective of delayed circadian rhythmicity. The patients took 5 mg of melatonin orally, 5 h before DLMO during 3 months.

Their responses to the checklist individual strength (CIS), a reliable questionnaire measuring the severity of personally experienced fatigue, were assessed twice with a 6-week interval immediately before the treatment and once after 3 months treatment.

In the pre-treatment period the fatigue sub-score improved significantly. After treatment, the total CIS score and the sub-scores for fatigue, concentration, motivation and activity improved significantly. The sub-score fatigue normalized in two of the 29 patients in the pre-treatment period and in eight of 27 patients during treatment. This change was significant.

In the patients with DLMO later than 22.00 hours (n=21) the total CIS score and the sub-scores for fatigue, concentration and activity improved significantly more than in the patients (n=8) with DLMO earlier than 22.00 hours. Melatonin may be an effective treatment for patients with CFS and late DLMO, especially in those with DLMO later than 22.00 hours.

 

Source: van Heukelom RO, Prins JB, Smits MG, Bleijenberg G. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion. Eur J Neurol. 2006 Jan;13(1):55-60. https://www.ncbi.nlm.nih.gov/pubmed/16420393

 

Sleep quality and psychological adjustment in chronic fatigue syndrome

Abstract:

Without specific etiology or effective treatment, chronic fatigue syndrome (CFS) remains a contentious diagnosis. Individuals with CFS complain of fatigue and poor sleep–symptoms that are often attributed to psychological disturbance.

To assess the nature and prevalence of sleep disturbance in CFS and to investigate the widely presumed presence of psychological maladjustment we examined sleep quality, sleep disorders, physical health, daytime sleepiness, fatigue, and psychological adjustment in three samples. individuals with CFS; a healthy control group; and individuals with a definite medical diagnosis: narcolepsy. Outcome measures included physiological evaluation (polysomnography), medical diagnosis, structured interview, and self-report measures.

Results indicate that the CFS sample had a very high incidence (58%) of previously undiagnosed primary sleep disorder such as sleep apnea/hypopnea syndrome and restless legs/periodic limb movement disorder. They also had very high rates of self-reported insomnia and nonrestorative sleep.

Narcolepsy and CFS participants were very similar on psychological adjustment: both these groups had more psychological maladjustment than did control group participants. Our data suggest that primary sleep disorders in individuals with CFS are underdiagnosed in primary care settings and that the psychological disturbances seen in CFS may well be the result of living with a chronic illness that is poorly recognized or understood.

 

Source: Fossey M, Libman E, Bailes S, Baltzan M, Schondorf R, Amsel R, Fichten CS. Sleep quality and psychological adjustment in chronic fatigue syndrome. J Behav Med. 2004 Dec;27(6):581-605. http://www.ncbi.nlm.nih.gov/pubmed/15669445

 

Sleep assessment in a population-based study of chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling condition that affects approximately 800,000 adult Americans. The pathophysiology remains unknown and there are no diagnostic markers or characteristic physical signs or laboratory abnormalities. Most CFS patients complain of unrefreshing sleep and many of the postulated etiologies of CFS affect sleep. Conversely, many sleep disorders present similarly to CFS. Few studies characterizing sleep in unselected CFS subjects have been published and none have been performed in cases identified from population-based studies.

METHODS: The study included 339 subjects (mean age 45.8 years, 77% female, 94.1% white) identified through telephone screen in a previously described population-based study of CFS in Wichita, Kansas. They completed questionnaires to assess fatigue and wellness and 2 self-administered sleep questionnaires. Scores for five of the six sleep factors (insomnia/hypersomnia, non-restorative sleep, excessive daytime somnolence, sleep apnea, and restlessness) in the Centre for Sleep and Chronobiology’s Sleep Assessment Questionnaire (SAQ) were dichotomized based on threshold. The Epworth Sleepiness Scale score was used as a continuous variable.

RESULTS: 81.4% of subjects had an abnormality in at least one SAQ sleep factor. Subjects with sleep factor abnormalities had significantly lower wellness scores but statistically unchanged fatigue severity scores compared to those without SAQ abnormality. CFS subjects had significantly increased risk of abnormal scores in the non-restorative (adjusted odds ratio [OR] = 28.1; 95% confidence interval [CI]= 7.4-107.0) and restlessness (OR = 16.0; 95% CI = 4.2-61.6) SAQ factors compared to non-fatigued, but not for factors of sleep apnea or excessive daytime somnolence. This is consistent with studies finding that, while fatigued, CFS subjects are not sleepy. A strong correlation (0.78) of Epworth score was found only for the excessive daytime somnolence factor.

CONCLUSIONS: SAQ factors describe sleep abnormalities associated with CFS and provide more information than the Epworth score. Validation of these promising results will require formal polysomnographic sleep studies.

 

Source: Unger ER, Nisenbaum R, Moldofsky H, Cesta A, Sammut C, Reyes M, Reeves WC. Sleep assessment in a population-based study of chronic fatigue syndrome. BMC Neurol. 2004 Apr 19;4:6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419502/  (Full article)

 

Monozygotic twins discordant for chronic fatigue syndrome: objective measures of sleep

Abstract:

PURPOSE: Chronic fatigue syndrome (CFS) is characterized by profound fatigue accompanied by disturbances of sleep, cognition, mood, and other symptoms. Our objective was to describe sleep architecture in CFS-discordant twin pairs.

METHODS: We conducted a co-twin control study of 22 pairs of monozygotic twins where one twin met criteria for CFS and the co-twin was healthy. Twins underwent two nights of polysomnography.

RESULTS: The percentage of Stage 3 and REM sleep was greater among the CFS twins than their healthy co-twins (P< or = .05 for both), but no other differences in sleep architecture including sleep latency, REM latency, and total sleep time were observed. Compared to their co-twins, CFS twins had higher values for the apnea-hypopnea index and apnea-hypopnea arousal index (P< or =.05 for both).

CONCLUSION: These results do not provide strong evidence for a major role for abnormalities in sleep architecture in CFS. Respiration appears impaired in CFS, but these clinical abnormalities cannot alone account for the prominence of sleep complaints in this illness. The co-twin control methodology highlights the importance of selecting well-matched control subjects.

 

Source: Ball N, Buchwald DS, Schmidt D, Goldberg J, Ashton S, Armitage R. Monozygotic twins discordant for chronic fatigue syndrome: objective measures of sleep. J Psychosom Res. 2004 Feb;56(2):207-12. http://www.ncbi.nlm.nih.gov/pubmed/15016580

 

First-night effect in the chronic fatigue syndrome

Abstract:

Since the magnitude of the first-night effect has been shown to be a function of medical conditions and of settings in which polysomnographies are performed, it is essential to evaluate the habituation phenomenon in each case in order to determine the optimal recording methodology. A first-night effect was evidenced in certain cases of chronic fatigue syndrome, but not in others.

To clarify this issue, a large group of patients with chronic fatigue syndrome who had no primary sleep disorders were selected and recorded for two consecutive nights in a hospital sleep unit. Several parameters, frequently associated with the first-night effect, were found to be influenced by the recording methodology: Total Sleep Time, Sleep Efficiency, Sleep Efficiency minus Sleep Onset, Sleep Onset Latency, Wake Time, Slow Wave Sleep, Rapid Eye Movement Sleep, Rapid Eye Movement Sleep Latency and Number of Sleep Cycles. Bland and Altman plots determined that the difference scores between the nights included a systematic bias linked to the order of recordings (first-night effect). Factorial analysis grouped the difference scores into three factors.

No significant difference was observed between patients with generalized anxiety comorbidity and those with no psychiatric comorbidity, or between those with and without psychiatric comorbidity. Chronic fatigue syndrome must thus be added on the list of conditions where a clinically significant habituation effect takes place.

 

Source: Le Bon O, Minner P, Van Moorsel C, Hoffmann G, Gallego S, Lambrecht L, Pelc I, Linkowski P. First-night effect in the chronic fatigue syndrome. Psychiatry Res. 2003 Sep 30;120(2):191-9. http://www.ncbi.nlm.nih.gov/pubmed/14527650

 

Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

STUDY OBJECTIVES: To examine the objective and subjective measures of insomnia in chronic fatigue syndrome (CFS).

DESIGN: Monozygotic co-twin control study.

SETTING: Academic medical center.

PATIENTS OR PARTICIPANTS: Twenty-two pairs of monozygotic twins where 1 member of the pair had CFS and the other did not.

INTERVENTIONS: N/A.

MEASUREMENTS AND RESULTS: Twenty-two CFS-discordant twin pairs completed a Sleep Disorders Questionnaire, overnight polysomnography, and a postpolysomnography sleep survey. Mean and percent differences in the sleep measures were compared between the CFS and healthy twins using matched-pair methods of analysis. Compared with their healthy co-twins, the CFS twins more frequently endorsed 8 subjective measures of insomnia and poor sleep (all p < or = 0.05). However, the CFS and healthy twins did not differ in objective polysomnographic measures of insomnia, including sleep latency, total sleep time, sleep efficiency, arousal number, arousal index, hypnogram awakenings, rapid eye movement (REM)-sleep latency, and percent stages 1, 2, and 3-4 (delta). Percent stage REM sleep was increased in the CFS twins compared with the healthy twins (27.7% vs. 24.4%, p < or = 0.05). On the postpolysomnography survey, CFS twins reported that they had slept fewer hours (6.2 vs. 6.7; p < or = 0.05), and were less well rested (p < or = 0.001) compared to their co-twins.

CONCLUSIONS: CFS patients had worse subjective sleep than their co-twins despite little objective data supporting this discrepancy, suggesting they suffer from an element of sleep-state misperception. The higher percentage of REM sleep in the CFS twins implies that REM sleep may play a role in this illness.

 

Source: Watson NF, Kapur V, Arguelles LM, Goldberg J, Schmidt DF, Armitage R, Buchwald D. Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome. Sleep. 2003 May 1;26(3):324-8. http://www.ncbi.nlm.nih.gov/pubmed/12749553

 

Health and functional status of twins with chronic regional and widespread pain

Erratum in: J Rheumatol. 2002 Dec;29(12):2667. Buchwald, Dedra [corrected to Buchwald, Debra].

 

Abstract:

OBJECTIVE: To examine the independent effects of chronic regional and widespread pain syndromes on health and functional status after accounting for comorbid chronic fatigue using a co-twin control design.

METHODS: We identified 95 twin pairs discordant for pain in which one twin had chronic regional or widespread pain and the other denied chronic pain. Demographic data, functional and psychological status, health behaviors, and symptoms based on the 1994 criteria for chronic fatigue syndrome (CFS) were assessed by questionnaire. Psychiatric diagnoses were based on structured interview. Random effects regression modeling estimated associations between chronic regional and widespread pain and each health measure with and without adjustment for CFS.

RESULTS: Significant differences (p </= 0.05) were found within twin pairs discordant for chronic regional and widespread pain, for general health perception, and physical and mental health functioning as measured by summary scores from the Short Form-36. In addition, differences were observed within pain discordant pairs in psychological distress as measured by the General Health Questionnaire as well as the number of psychiatric diagnoses. Adjustment for CFS eliminated the association between chronic pain and mental health, but the association between chronic pain and poor general health, physical functioning, and sleep quality persisted (p </= 0.01). Only the intra-pair difference in physical functioning distinguished twins with regional vs widespread pain (p </= 0.05).

CONCLUSION: Both chronic regional and widespread pain exact debilitating effects on perceived general health, physical functioning, and sleep quality independent of CFS. However, the psychological and psychiatric influence of chronic pain appears closely tied to CFS. Research should examine the additive role of CFS-like illnesses in patients with chronic pain, and its influence on treatment and outcome.

 

Source: Aaron LA, Arguelles LM, Ashton S, Belcourt M, Herrell R, Goldberg J, Smith WR, Buchwald D. Health and functional status of twins with chronic regional and widespread pain. J Rheumatol. 2002 Nov;29(11):2426-34. http://www.ncbi.nlm.nih.gov/pubmed/12415604

 

Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions

Abstract:

In humans, activation of the primary host defense system leads to increased or decreased NREM sleep quality, depending on the degree of early immune activation. Modest elevations of certain inflammatory cytokines are found during experimental sleep loss in humans and, in addition, relatively small elevations of cytokines are seen following commencement of pharmacological treatments with clozapine, a CNS active antipsychotic agent, known to have immunomodulatory properties. Cytokines such as TNF-alpha, its soluble receptors, and IL-6, present in the periphery and the CNS, comprise a link between peripheral immune stimulation and CNS-mediated behaviors and experiences such as sleep, sleepiness, and fatigue. The debilitating fatigue experienced in chronic fatigue syndrome and related diseases may also be related to altered cytokine profiles.

 

Source: Mullington JM, Hinze-Selch D, Pollmächer T. Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions.  Ann N Y Acad Sci. 2001 Mar;933:201-10. http://www.ncbi.nlm.nih.gov/pubmed/12000021