Comparison of Subjective and Objective Measures of Insomnia in Monozygotic
Twins Discordant for Chronic Fatigue Syndrome
Nathaniel F. Watson, MD1; Vishesh Kapur, MD, MPH2; Lester M. Arguelles, MS3; Jack Goldberg, PhD4; Douglas F. Schmidt, PhD5; Roseanne Armitage, PhD6; Dedra
Buchwald, MD7
1Department
of Neurology and Sleep Disorders Center, University of Washington; 2Department of Medicine and Sleep Disorders Center, University
of Washington; 3Epidemiology and Biostatistics Division, University of Illinois at Chicago; 4Department of Epidemiology, University of Washington
and VA Vietnam Era Twin Registry, Seattle, WA; 5Virginia Mason Sleep Disorders Center, Seattle, WA; 6Department of Psychiatry and Sleep Study
Unit, University of Texas Southwestern Medical Center at Dallas; and the 7Department of Medicine, University of Washington
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 ≤ 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 move-
ment (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 ≤ 0.05). On the postpolysomnography
survey, CFS twins reported that they had slept fewer hours (6.2 vs. 6.7; p
≤ 0.05), and were less well rested (p ≤ 0.001) compared to their co-twins.
Conclusions: CFS patients had worse subjective sleep than their cotwins 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.
Key Words: chronic fatigue syndrome, monozygotic, twins, insomnia,
polysomnography
Citation: Watson NF, Kapur V, Arguelles LM et al. Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome. SLEEP 2003;26(3):324-8.
INTRODUCTION
sleep quality, exhibit strong heritability.7 Polysomnography (PSG) in
twins also has shown that body movements, stage 2, slow wave sleep
(stages 3 and 4), and rapid eye movement (REM) density are all largely
genetically determined.8-11 Genetic similarities make twin studies useful
for detecting subtle environmental effects when studying diseases of
unknown etiology; when the appropriate control group is unknown; or
when the domain of interest, such as sleep, is under genetic influence.12
The purpose of the current study was to examine objective and subjective measures of sleep disturbances in monozygotic twins where 1 twin
had CFS and the other twin did not. This co-twin control design effectively controls for genetic variability in sleep disturbances. We hypothesized that CFS twins would have more insomnia-related complaints than
their healthy co-twins but that objective measures of sleep quality would
not differ substantially.
CHRONIC FATIGUE SYNDROME (CFS) IS A HETEROGENEOUS
DISORDER OF EXCESSIVE FATIGUE OF GREATER THAN 6
MONTHS’ DURATION IN THE ABSENCE OF A CLEAR PHYSICAL
OR PSYCHIATRIC ETIOLOGY.1 Unrefreshing sleep is 1 of 8 possible
symptom criteria for this syndrome.1 Many individuals with CFS suffer
from insomnia, defined as a disorder of initiating and maintaining sleep.2
The inability to fall or stay asleep, inadequate sleep time, feeling unrested on rising, and sleepiness are among the most frequent complaints of
CFS patients.3-5 In prior studies, however, the unrefreshing sleep suffered by patients with CFS has typically been unconfirmed by objective
means or its association with objective abnormalities was poorly
described. For example, CFS patients have been shown to exhibit
polysomnographic characteristics of poor sleep, such as low sleep efficiency and more time awake after sleep onset,6 but the precise relationship of these objective findings to perceptions of sleep were not examined. In some cases, primary sleep disorders have been detected in these
patients.3,4
Twin studies of sleep indicate that subjective reports of sleep, including daytime napping, habitual bedtime, sleep duration, and subjective
METHODS
Registry Construction and Subject Recruitment
Twins were recruited through patient support-group newsletters
(58%), electronic bulletin board notices for CFS (15%), physicians and
researchers familiar with CFS (11%), twin organizations and researchers
(6%), relatives and friends (3%), and other sources (8%). A total of 600
twins were mailed an intake questionnaire, 426 (71%) were returned,
and complete intake data were available for both members of 193 twin
pairs. Each twin filled out a questionnaire on demographics, zygosity,
habits, lifestyle, distress, physical health conditions, and a checklist of
the symptoms of CFS.1 For the nonfatigued twin, a control version of
questions was used that did not reference fatigue. A more complete
description of the Registry can be found elsewhere.13 Informed consent
was obtained on all Registry participants in accordance with our institution’s Human Subjects Office.
Disclosure Statement
This work was funded by grant U19AI38429 from the National Institutes of
Health (Dr. Buchwald).
Submitted for publication May 2002
Accepted for publication December 2002
Address correspondence to: Nathaniel F. Watson, MD, University of Washington Sleep Disorders Center, Box 359803, 325 Ninth Avenue, Seattle, WA
98104-2499; Tel: 206-731-4999; Fax: 206-731-5657; E-mail: [email protected]
SLEEP, Vol. 26, No. 3, 2003
324
Subjective and Objective Measures of Insomnia—Watson et al
Psychiatric Disorders
Sleep latency was defined as lights out to the first epoch of any 3 consecutive epochs of sleep or to the first epoch of stage 2, 3, 4, or REM,
whichever came first. REM latency was defined as sleep onset to the
first epoch of REM sleep. Hypnogram awakenings represented the total
number of awakenings for the night as calculated by a sleep medicine
physician (NFW) tallying the number of times the patient went from a
stage of sleep to wakefulness for at least 1 epoch, as evident on the postPSG hypnogram. We also evaluated each twin for clinically significant
sleep disorders, such as obstructive sleep apnea or periodic limb movement disorder; none were evident.
Post-PSG Survey. The morning following the PSG night, a brief survey was administered to all twins. This survey asked the twins to subjectively report their total sleep time and the number of times they awakened during the night. In addition, they were asked if they slept well and
if they felt rested.
The Diagnostic Interview Schedule Version III-A,14 a structured interview based on the Diagnostic and Statistical Manual of Mental Disorders, Version III-Revised,15 was administered by telephone to all Registry twins. Sections included major depression, dysthymia, generalized
anxiety, panic, agoraphobia, posttraumatic stress disorder, mania, bipolar disorders, schizophrenia, eating disorders, somatization, and substance abuse and dependence.
Selection of the Clinical Sample
From the Registry, 22 sets of monozygotic twins were chosen for a 6day evaluation. Twins were required to: 1) be at least 18 years of age; 2)
have been reared together; 3) be discordant for CFS (ie, 1 twin met the
Centers for Disease Control and Prevention criteria and the other was
healthy and denied chronic fatigue); 4) provide evidence of a recent negative HIV-1 antibody test; 5) discontinue alcohol, caffeine, and all medications known to affect sleep, cognition, and immune function at least
2 weeks prior to the evaluation; and 6) be able to travel to Seattle at the
same time.
Both the ill and the healthy twins were rigorously screened. CFS was
defined in accordance with the Centers for Disease Control and Prevention CFS criteria.1 For fatigued twins, the symptom checklist and diagnoses generated by the Diagnostic Interview Schedule were used to
determine whether CFS criteria were initially met. Next, all medical
records for the previous 5 years were reviewed by an internist for exclusionary conditions. Health issues were resolved by telephone or physician contact. Laboratory tests were performed prior to the evaluation. A
psychologist and an infectious disease specialist independently reviewed
the charts and approved the twins for participation. Just before the
scheduled visit, screening questions were readministered to document
that the ill twin still met CFS criteria and the co-twin was healthy.
Monozygosity was initially determined using previously validated selfreport methods16,17 and confirmed using molecular biology techniques.18
Measurement of Mood
The Positive and Negative Affect Schedule (PANAS)21 was used to
obtain a continuous measure of current mood from all twins. This instrument asks subjects to rate the intensity with which they have experienced
20 emotions or feelings within the last 10 minutes from 1 (not at all or
very slightly) to 5 (extremely). The responses yield 2 scales: positive and
negative affect. The PANAS was used to adjust for mood in the analysis.
Statistical Analysis
Mean levels of the sleep measures in CFS and healthy co-twins were
compared using a paired t-test. As an indicator of familial clustering for
the continuously distributed objective sleep measures, we used the intraclass correlation coefficient derived from mixed-effects regression
modeling for twin data.22 Values of this statistic that are close to +1.0
indicate a strong familial influence on the phenotype. Subjective data
from the Sleep Disorders Questionnaire were dichotomized, where twins
answering disagree or never or rarely were combined into a single “no”
group and twins answering sometimes, usually, or true or always were
combined into a single “yes” group. Analysis was performed via the
signed-rank test. For categorical measures derived from the post-PSG
survey, percentages were estimated in the CFS and healthy co-twins; formal statistical testing used McNemar’s chi-square test. We also repeated
all our analyses after using the PANAS scales to adjust for the effects of
positive and negative mood. These analyses used regression methods
and, since in no case did the adjustment make a difference in the findings, we present only the unadjusted results.
Measures of Sleep
The assessment of sleep and insomnia had 3 components: a Sleep Disorders Questionnaire, 2 nights of PSG, and a post-PSG survey of sleep.
Each is described in detail below.
Sleep Questionnaire. Both twins filled out a 175-item Sleep Disorders Questionnaire that explores a person’s subjective themes or beliefs
regarding sleep.19 The following 8 items were selected for use in this
study based on their relevance to insomnia: “I often have a poor night’s
sleep,” “I wake up often during the night,” “My night’s sleep is often
restless and disturbed,” “I feel that my sleep is abnormal,” “I have trouble getting to sleep at night,” “I have been unable to sleep at all for several days,” “I feel that I have insomnia,” and “I take a prescription drug
to help me sleep.” The response categories for these items are 1 = disagree or never, 2 = rarely, 3 = sometimes, 4 = usually, 5 = true or always.
Polysomnography. PSG with a full recording montage was performed during 2 nights, including central and occipital electroencephalogram, left and right electrooculogram, mental and submental
electromyogram, chest and abdominal respiratory effort, nasal and oral
airflow, left and right anterior tibialis electromyogram, pulse oximetry,
electrocardiogram, body position, and microphone-detected snoring.
Data were recorded on an ALICE 3™ digital system (Respironics/
Healthdyne Technologies, Murrysville, PA 15668-8550). Visual PSG
scoring was performed according to standard Rechtschaffen and Kales
criteria by a single technician blinded to illness status.20 All data were
derived from the second night, with the first night being used for
acclimatization to the sleep-lab environment. Twins had traveled to Seattle at least 4 nights prior to the acclimatization night and 5 nights prior
to the study night. The following sleep-related parameters were calculated: total sleep time, sleep latency, REM latency, sleep staging, sleep
efficiency, hypnogram awakenings, arousal number, and arousal index.
SLEEP, Vol. 26, No. 3, 2003
RESULTS
Subject Recruitment and Selection
Of 193 twin pairs screened, 119 (62%) were discordant for 6 or more
months of fatigue. Of these, 67 (56%) were monozygotic and had complete data available; however, 14 fatigued twins had a CFS exclusionary
psychiatric illnesses, 4 had a CFS exclusionary medical disorder, 1 had
a body mass index greater than 45, and 9 did not meet CFS symptom criteria. In 4 pairs, the nonfatigued twin had a condition exclusionary for
CFS (eg, cancer), and 6 additional pairs were excluded for other reasons
(eg, inadequate English, pregnancy). Of the 29 remaining pairs in which
1 twin met the criteria for CFS and their co-twin was healthy and denied
chronic fatigue, 22 (76%) completed the study, 1 (3%) refused, 2 (7%)
could not be scheduled, and 4 (14%) could not discontinue medications.
There were no differences in measures of physical or mental functioning
as assessed by the SF-36® Health Survey23 between the 22 twin pairs
with CFS who traveled to Seattle and the 7 who did not.
Demographic and Clinical Characteristics
The twins’ mean age at the time of the study was 41.4 years, 20 pairs
325
Subjective and Objective Measures of Insomnia—Watson et al
were female, and all were white and raised together. There were no differences between the CFS and healthy twins in the proportion that were
married (59% vs. 59%). A small, statistically significant difference in the
average years of schooling (CFS 14.0 vs. healthy 14.7; P ≤ 0.05) was
noted. The CFS twins had a mean duration of illness of 7.0 years.
twins (27.7 vs. 24.4, p ≤ 0.05); it is noteworthy that the healthy co-twins
had a generous percentage of REM sleep compared to published normative values.24 The strong degree of familial clustering for the objective
sleep measures was evident from the magnitude of the intraclass correlations, most of which were greater than 0.60.
Sleep Questionnaire
Post-PSG Survey
There were significant differences in all 8 measures of insomnia from
the Sleep Disorders Questionnaire (Table 1). The largest effects
observed were for the use of a prescription drugs for sleep, trouble getting to sleep at night, waking up often during the night, and feelings that
sleep is abnormal, poor, restless, and disturbed. More modest differences
between twins were noted for the inability to sleep for several days and
feelings of insomnia.
The post-PSG survey (Table 3) revealed that, compared to their cotwins, the CFS twins reported that they had slept fewer hours (6.2 vs.
6.7, p ≤ 0.05), were less well rested upon awakening (68% vs. 15%, p ≤
0.001), and felt their sleep was worse compared to their normal night’s
sleep (42% vs. 15%, p = 0.06). The 2 groups did not differ on the subjective number of awakenings (2.3 vs. 1.9, p = 0.30).
DISCUSSION
Polysomnography Measures
Virtually all of the objective measures of sleep obtained from the PSG
were remarkably similar in both the CFS and healthy twin pairs (Table
2). For example, the mean total sleep time was 6.3 hours for both the
CFS and healthy twins. The overall index of sleep efficiency was virtually identical in the CFS (88.3%) and healthy co-twins (88.6%). Twins
with CFS did have a higher percentage of REM sleep than did their coTable 1—Selected subjective measures of sleep from the Sleep Disorders Questionnaire
Subjective Measures
CFS Twins Healthy Twins
(% yes)
(% yes)
I wake up often during the night
My nights sleep is often restless and disturbed
I feel that my sleep is abnormal
I have trouble getting to sleep at night
I have been unable to sleep at all for several days
I feel that I have insomnia
I often have a poor nights sleep
I take a prescription drug to help me sleep
81.8
81.8
86.4
72.7
18.2
31.8
86.4
61.9
31.8
19.1
9.5
22.7
0.0
4.8
27.3
0.0
P value
≤0.001
≤0.001
≤0.001
≤0.001
≤0.05
≤0.01
≤0.001
≤0.001
Twins answering disagree or never or rarely were combined into a single “no” group; twins
answering sometimes, usually, or true or always were combined into a single “yes” group.
All statistical tests are signed-rank tests.
Table 2—Objective measures of sleep obtained from polysomnography
Measures
CFS Twins
Mean (95% CI)
Total sleep time (hours)
6.3 (5.9 - 6.7)
Arousal number
111.7 (84.3 - 139.0)
Arousal index
17.9 (13.6 – 22.3)
(arousals/hour of sleep)
Hypnogram awakenings
25.9 (20.7 – 31.1)
% Stage 1
8.3 (5.4 - 11.3)
% Stage 2
44.9 (41.4 – 48.4)
% Stage 3-4
19.1 (15.4 – 22.9)
27.7 (24.6 – 30.7)
% Stage REM1
Sleep efficiency
88.3 (83.4 – 93.1)
REM sleep latency (min)
63.5 (41.1 – 86.0)
Sleep latency (min)
13.6 (7.8 - 19.4)
Healthy Twins
Mean (95% CI)
Intraclass
Correlation
6.3 (6.0 - 6.8)
116.1 (88.7 - 143.4)
18.6 (14.2 - 22.9)
0.74
0.61
0.71
27.1 (21.9 - 32.4)
9.0 (6.1 - 12.1)
49.0 (45.5 - 52.5)
17.5 (13.7 - 21.3)
24.4 (21.3 - 27.5)
88.6 (83.7 - 93.4)
88.0 (65.5 - 110.5)
10.6 (4.8 - 16.4)
0.63
0.72
0.21
0.72
0.65
0.69
0.13
0.15
CFS, chronic fatigue syndrome; CI, confidence interval; REM, rapid eye movement
1p ≤ 0.05
Table 3—Selected measures from the postpolysomnography survey
Measure
CFS Twin (CI)
Do you feel rested now?
68.0* (43.2 - 94.3)
Do you feel that you slept well?
42.1* (17.7 - 66.6)
How many hours do you think you slept last night?
6.2‡ (5.7 - 6.7)
How many times did you wake up during the night?
2.3‡ (1.7 - 2.9)
Healthy Twin (CI)
15.0* (0 - 32.1)
15.0* (0 - 32.1)
6.7‡ (6.2 - 7.2)
1.9‡ (1.3 - 2.5)
CFS, chronic fatigue syndrome; CI = 95% confidence interval; * % no response; ‡mean
SLEEP, Vol. 26, No. 3, 2003
326
A striking finding in this study was the propensity of the CFS twins to
report diverse symptoms of poor sleep in the absence of objective sleep
pathology. In particular, they had more complaints compatible with
insomnia compared to their healthy co-twins despite a sleep latency that
was both normal and similar to that of the healthy twins. Similarly, twins
with CFS reported more nighttime awakenings and more disturbed, restless, abnormal, and poor sleep than did their healthy co-twins in spite of
similar arousal indexes, sleep efficiencies, sleep architecture, and total
sleep time. Finally, the CFS twins were more likely to take prescription
drugs to help them fall asleep. These findings agree with previous studies indicating that CFS patients have poor subjective sleep3-6 but are
inconsistent with reports of increased sleep latency, reduced total sleep
time and sleep efficiency, and decreased stage REM sleep in patients
with CFS.2,25,26 Our use of a control group that accounts for familial
influences on sleep, the discontinuation of medications that interfere
with sleep for at least 2 weeks, and the performance of the PSG under
the same conditions on the same nights might explain why our findings
differ from those of previous investigations.
An increased percentage of REM sleep and a clinical, though not statistically significant, shortening of REM latency was observed in the
CFS group. This suggests that increased REM pressure is associated
with CFS, either as a predisposing factor or a consequence of the illness.
Of interest, previous twin studies have demonstrated that environmental,
rather than genetic, influences contribute to REM-stage variability.9 Possible explanations for increased percentage stage REM in the ill twins
include depression and primary sleep deprivation. Short REM latencies,
increased REM-sleep density, and an increased percentage of REM sleep
have been associated with depression,27 and depression is common in
patients with CFS.28 Although we controlled for current mood with the
PANAS in our analysis, this instrument does not provide diagnostic
information. Thus, we cannot completely exclude comorbid major
depression as contributing to the increase in REM sleep. These findings
deserve further investigation.
Insomniacs tend to underestimate total sleep time and overestimate
sleep-onset latency.29 Individuals with subjective insomnia despite
objectively normal sleep are considered to have sleep-state misperception, the cause of which is unknown.30 The minimal criteria for the diagnosis of sleep-state misperception according to the International Classification of Sleep Disorders-Revised requires a complaint of insomnia
despite normal sleep quality and duration.31 The CFS twins’ insomnia
complaints were contrary to their normal sleep latencies, sleep
efficiencies, and arousal indexes on PSG. Therefore, although
there is not a misperception of sleep duration, as indicated by
the CFS twins’ accurate estimation of total sleep time on their
P
post-PSG survey, there is a misperception of sleep quality. As
≤ 0.001
a result, we feel the CFS twins suffer from an element of
0.06
sleep-state misperception.
≤ 0.05
Previous studies have suggested that sleep-state mispercep0.30
tion may be a transitional state of sleep dysfunction between
normal sleep and the disturbed pattern of objective insomSubjective and Objective Measures of Insomnia—Watson et al
nia30,32 and may also be associated with metabolic alterations.32 Others
have observed that longer periods of wakefulness following sleep onset,
greater self-perceived sleep impairment, and current psychopathology
influence sleep-time estimation.33 Since beta and gamma activity, which
is associated with cognitive processes, is enhanced in insomnia at sleep
onset, a recent model of sleep-state misperception has proposed that
insomniacs experience a level of information and memory processing
that blurs the distinction between sleep and wakefulness and thereby
influences perceptions of sleep initiation and duration.34 Taken together,
these investigations indicate that physiologic aberrations, sleep quality
itself, and psychological factors may all affect the concordance of subjective and objective indexes of sleep.
One aspect of this study that deserves mention is our use of illnessdiscordant twins. Self-reported data have shown that hereditary factors
are important in determining sleep patterns such as daytime napping,
habitual bedtime, and sleep duration.7 A significant genetic contribution
also has been found in the self-reported problems of trouble falling
asleep, trouble staying asleep, waking often, and waking up tired.35 Likewise, twin studies have shown that sleep-onset latencies, awakening
measures, sleep length, sleep-stage changes, stage 2 sleep, slow wave
sleep (stages 3 and 4), and measures of REM sleep are all under genetic
control.8,10,36 The striking similarity of sleep architecture between members of our twin pairs, as reflected by large intraclass correlation coefficients, is particularly noteworthy and likely reflects heritable influences
on sleep. Because the co-twin design provides excellent control for
background variation of electroencephalographic activity and, hence,
maximizes the detection of abnormalities, our study provides strong evidence of sleep-state misperception in CFS.
This co-twin control study has several limitations. First, solicitation
by advertisement resulted in a volunteer sample of twin pairs with the
potential for ascertainment problems. However, the more desirable strategy of identifying twins from a population-based twin registry is not
possible in the United States. Thus, how representative the twins in this
study were of either twins in general or of persons with CFS is not
known. Second, chronic sleep habits prior to the study or travel to the
study site (eg, jet-lag) may have affected our data in unknown ways.
Likewise, we cannot rule out differences between twin pairs in objective
parameters of sleep that are subtle and unmeasured, yet important. Third,
our ALICE 3™ digital scoring system lacked a verified algorithm to
quantify alpha intrusion, a controversial measure of arousal observed not
only in CFS,25,37 fibromyalgia38,39 and insomnia,40 but also in pregnant
women41 and healthy individuals.38,42 Thus, it is possible that alpha intrusion may be related to the discordance between subjective and objective
sleep in the CFS twins. Finally, although we can rule out confounding
due to genetic factors, we cannot establish the temporal relationship
between physiologic parameters of sleep, perceived insomnia, and CFS.
In conclusion, twins with CFS had more complaints of insomnia than did
their healthy co-twins despite remarkably similar objective measures of
sleep. The higher percentage of REM sleep observed in the CFS twins
may point to high REM pressure as a predisposing factor for, or consequence of, CFS. The mismatch between subjective and objective measures of sleep described here are consistent with an element of sleepstate misperception. A final caveat is that studies such as this one cannot
address questions of mechanisms and etiology. Thus, the biologic and
psychosocial underpinnings of the sensation of disrupted sleep in CFS
remain to be elucidated.
REFERENCES
ACKNOWLEDGMENTS
33.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
The authors would like to thank the participants in the University of
Washington CFS Twin Registry for their cooperation, patience, and
goodwill. We also wish to acknowledge our Advisory Panel, who with
sage advice and ongoing encouragement improved our scientific efforts.
Finally, we would like to acknowledge Mary Fischer, MS, and Suzanne
Ashton, BS, for their assistance and helpful suggestions throughout this
project.
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36.
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