Exercise Capacity in Chronic Fatigue Syndrome
Archives of Internal Medicine
Vol. 160 No. 21, November 27, 2000
Pascale De Becker, PhD;
Johan Roeykens, PT; Masha Reynders, PT;
Neil McGregor, MD, PhD;
Background Patients with chronic
fatigue syndrome (CFS) suffer from various symptoms, including debilitating
fatigue, muscle pain, and muscle weakness. Patients with CFS can experience
marked functional impairment. In this study, we evaluated the exercise capacity
in a large cohort of female patients with CFS.
Methods Patients with CFS and matched sedentary control subjects performed a
maximal test with graded increase on a bicycle ergometer. Gas exchange ratio
was continuously measured. In a second stage, we examined only those persons
who achieved a maximal effort as defined by 2 end points: a respiratory
quotient of at least 1.0 and an age-predicted target heart rate of at least
85%. Data were assessed using univariate and multivariate statistical methods.
Results The resting heart rate of the patient group was higher, but the maximal
heart rate at exhaustion was lower, relative to the control subjects. The
maximal workload and maximal oxygen uptake attained by the patients with CFS
were almost half those achieved by the control subjects. Analyzing only those
persons who performed a maximal exercise test, similar findings were observed.
Conclusions When compared with
healthy sedentary women, female patients with CFS show a significantly
decreased exercise capacity. This could affect their physical abilities to a
moderate or severe extent. Reaching the age-predicted target heart rate seemed
to be a limiting factor of the patients with CFS in achieving maximal effort,
which could be due to autonomic disturbances.
Arch Intern Med. 2000;160:3270-3277
A DIAGNOSIS of chronic fatigue
syndrome (CFS), as defined in 19941 by the
Centers for Disease Control and Prevention (CDC), Atlanta, Ga, requires unexplained
fatigue for more than 6 months not due to continuing exertion, not resolved by
rest, and accompanied by 4 or more of the following 8 symptoms: sore throat,
tender lymph nodes, memory and concentration problems, joint pain, headache of
a new type, unrefreshing sleep, and postexertional malaise lasting more than 24
hours. Chronic fatigue syndrome is
characterized as a new onset of fatigue, serious enough to reduce daily
activities by more than 50% and in the absence of any other medically identifiable
disorders.1,
2 Patients with CFS exhibit marked impairment
and sometimes have greater degrees of functional disability than do patients
with other diseases such as type 2 diabetes mellitus, congestive heart failure,
hypertension, acute myocardial infarction, major depression, relapsing or
remitting multiple sclerosis,3 and
acute infectious mononucleosis.4
Various studies have evaluated the
ability of patients with CFS to perform exercise, but conflicting results have
been published.5-10 Some authors believe the aerobic capacity of
patients with CFS lies within the low normal range,6, 8, 9 whereas
others report a reduced aerobic capacity relative to normal subjects5, 10 and
to patients with irritable bowel syndrome.7 Taking into account that the population with
CFS is very heterogeneous, these different findings could be due to a selection
bias, the low number of individuals studied, or both.
The aerobic potential of an
individual is determined by cardiac output and muscle oxidative capacity. Muscle contractility also plays a very
important role.11 Previous studies have considered whether
these factors limit the ability to complete physically active tasks in CFS.9, 12-17 Although patients report significant
reductions in physical capabilities and postexertional symptom exacerbation,12, 17
findings from their tests of muscle strength, endurance, and function are
normal.9,
12, 17-21 Histological and metabolic studies give
mixed results. Several studies of
patients with CFS have shown reductions in muscle oxidative capacity and
metabolism,16,
22
atrophy of the fast twitch fibers,23-25
mitochondrial abnormalities,23, 24, 26
increased lactic acid production during exercise,13-15
and myopathic features on single fiber electromyogram.27
However, these abnormalities are
not consistent, contributing to the consensus that CFS is a heterogeneous
disorder and that differences in patient populations and muscles studied may
account for discrepancies between studies.28 Some authors believe that central rather
than peripheral factors are responsible for the reduced physical capacity and the
difficulty in performing a maximal effort.9, 11, 17, 29 Patients with CFS have exhibited
repetitively negative changing T waves at Holter registrations30 and
a slow acceleration of heart rate during exercise.10 It
is suggested that the fatigue in CFS may be related to subtle cardiac
dysfunction occurring at workloads common to ordinary living.30
The pathophysiology of exercise
has been studied extensively in relation to cardiovascular, pulmonary,
endocrine, and neuromuscular diseases, but little information exists on the
interrelationship between physical exercise parameters and CFS.31 As there is only scant information on the
physical capacity of patients with CFS, physicians who are called on to assist
in the determination of the physiological capacity of these patients have no
standards to rely on. The few studies
that have been done involve limited numbers of patients, which could bias the
results considering the heterogeneity of the CFS population. Therefore, we judged it necessary to study a
large group of patients to be able to draw conclusions on their exercise
capacity and degree of impairment.
The standard for measuring
exercise capacity has always been the maximal oxygen uptake (VO2max)
during high intensity whole body exercise.11, 32 It is generally accepted that
cardiopulmonary exercise testing is a good research tool for this purpose33 and
is commonly used to determine an individual's exercise potential.34
We designed a maximal bicycle
ergometric test against a graded increase in workload, which aimed to collect
data regarding exercise capacity in a large cohort of female patients with
CFS. These results were compared with a
population of sedentary control female subjects and with findings reported in
the literature on other sedentary healthy populations.
PATIENTS AND
CONTROL SUBJECTS
A total of 450 consecutive female patients who met the CDC's 1988 or 1994
criteria for CFS were enrolled in the study, which had been approved by an
ethical committee. Of these, 427 met
the requirements and agreed to participate.
The diagnosis of CFS was made by patient history, routine physical
examination, and laboratory test results to exclude other relevant diagnoses,
as recommended by Fukuda et al.1
A group of 204
age-matched sedentary women served as a control population. We selected them from subjects who came for
medical checkups. Only those who did sitting
work and performed a maximum of 1 hour of sports per week were included. Control subjects were accepted into the
study only if they denied having symptoms of chronic fatigue and did not suffer
from any medical conditions known to cause chronic fatigue.
STUDY DESIGN
All patients and controls underwent a bicycle ergometric test against a graded
increase in workload until exhaustion.
The exercise tests were performed at room temperature (20°C-22°C) and at
a humidity of 40% to 60%. The subjects
assumed the sitting position on the electromagnetically braked ergometer
(Jaeger 900; Lode B.V., Groningen, the Netherlands), and the test was started
after 3 to 5 minutes of adjustment.
Heart rate was continuously monitored at rest and during exercise .
There was continuous recording of the 12-lead electrocardiogram using an
electrocardiograph (Marquette Electronics Inc, Milwaukee, Wis). An open circuit spirometer (Mijnhart Oxycon;
IBM, Bunnik, the Netherlands) with automatic printout every 30 seconds was used
to collect pulmonary data during the test.
As such, data for VO2max and maximal carbon dioxide
production were averaged for every 30-second interval during each stage.
Expired air was collected via a 2-way breathing valve attached to a mask that
covered the subject's nose and mouth and was analyzed continuously for
ventilatory and metabolic variables.
Before each test, the spirometer was calibrated for ambient conditions.
The increments
were chosen to obtain a total exercise duration between 8 and 12 minutes, which
is suggested as an optimal test period.34 Thus, the duration of exercise was kept
below 15 minutes to avoid possible early onset fatigue in the lower limbs
because of lack of physical fitness.
The patients with CFS started at 10 W, with an increase of 10 W/min. The control population began at 40 W, with
an increase of 30 W every 3 minutes.
The following
parameters were measured: heart rate at rest (HRrest), maximal heart rate
(HRmax), maximal work capacity attained, VO2max per kilogram of body
weight, maximal respiratory quotient (RQmax), heart rate at RQ of 1.0 (HRAT),
peak work rate at RQ of 1.0 (WAT), and the percentage of target heart rate
(THR) that was achieved. The metabolic
data analyzed were the means of the last 30 seconds from the final stage of
exercise or the highest value attained if a decline in VO2 occurred
at the final workload.
A separate
analysis between patients and controls was done with all those who performed a
maximal exercise test. The criteria
used for determining whether the subject had attained a physiological maximum
were the accomplishment of 2 end points: (1) an RQ greater than 1.0 and (2)
reaching at least 85% of the age-predicted THR. The HRmax achievable during exercise of large muscles (eg, with
use of a bicycle ergometer) is generally equivalent to 220 minus the subject's
age in years, plus or minus 20 beats per minute.35
Data were sent
to Neil McGregor, MD, PhD, at the University of Newcastle, Australia, for
independent analysis to reduce any possibility of bias.
STATISTICAL
ANALYSIS
Data distributions were evaluated for violations of assumptions with parametric
statistical analyses. The percentage of
THR was arcsine transformed, while all other exercise response variables were
log transformed to improve normality and linearity. Subject characteristics were assessed using x2
probability and t tests. Univariate group differences were evaluated
on untransformed data using the nonparametric Mann-Whitney test. Multivariate group differences were
determined on transformed data using standard and forward stepwise discriminant
function analyses. Pearson product
moment correlation was used to investigate within-group differences in the
associations between variables. These
data were processed using statistical software (Access97 and Excel97;
Microsoft, Redmond, Wash, and Statistica, version 5.1; Statsoft, Tulsa, Okla).
There was no difference in age
between the patients with CFS and the control subjects (mean + SD years, 37.0 +
9.0 and 35.9 + 9.2, respectively). All
individuals in the study were white Europeans.
Those with CFS had a mean illness duration of 7.0 + 6.4 years.
Discriminant function analysis
was applied to determine the major characteristics that differentiated between
the exercise response profiles of the CFS vs the control subjects. Table 1 shows that the regression model revealed a large
deviation in the response characteristics between them (Wilks λ= 0.14, F = 199.4; P<.001), with a
high degree of homogeneity within the 2 groups. Most (97.8%) of the control subjects complied with the control
model profile, and 99.7% of individuals with CFS complied with the CFS group
profile. Univariate analysis showed
that 10 of the 15 exercise profile measures were reduced in those with CFS
compared with the control subjects and 1 parameter (HRrest) was increased.
Forward stepwise discriminant
function analysis was used to assess the major parameters that determined the
different response characteristic profiles in the CFS vs the control
groups. A strong model was found (Wilks
λ = 0.136, F = 301.3), with HRAT being the
primary discriminating variable, followed by WAT and the maximal workload per
kilogram of body weight (P<.001 for all). Thus, the exercise response characteristics of the CFS and the
control subjects were very dissimilar, principally in HRAT and WAT.
Pearson product moment correlation
analysis was undertaken to assess any differences in the exercise parameters
between the 2 groups to allow a better understanding of how exercise capacity
varied. Table 2 summarizes the correlation comparisons between WAT
and HRAT with the heart rate parameters and RQ in the patients with CFS vs the
control subjects. There was a
significant disregulation of the relationships between WAT and HRAT with
disregulation of the heart rate parameters.
Therefore, variation in heart rate was strongly related to changes in
exercise capacity in the patients with CFS.
Figure 1 shows the comparative scatterplot of WATand HRAT in
the 2 groups. While there was a similar
correlation between WAT and HRAT (CFS, r = 0.50; control, r =
0.56; P<.001 for both), there was a large reduction in both
parameters in the patients with CFS (Table 1). Figure 2, Figure 3, and Figure 4 illustrate the association between HRAT and WAT, VO2max,
and exercise duration in the patients with CFS and in control subjects. These figures demonstrate that the
relationships between these 3 factors were quite different in the 2 groups.
The maximal respiratory quotient
was positively correlated with exercise duration, HRmax, and the percentage of
THR in both groups (all r >0.25;
P<.001). In the patients with
CFS, RQmax was positively associated with WAT(r = 0.26; P<.001) and negatively
associated with HRAT (r =
-0.15; P<.01). In the control
individuals, RQmax was positively correlated with HRrest (r = 0.17; P<.02) and negatively
correlated with WAT(r =
-0.24; P<.002).
The percentage of THR was
positively associated with exercise duration, HRrest and HRmax, maximum
workload, VO2max, HRAT and WAT, and RQmax in both groups (all r >0.25; P<.001). In the control subjects, the percentage of
THR was negatively correlated with the THR (r = -0.16; P<.04). In those with CFS, the percentage of THR had
a statistically higher correlation coefficient for WAT (CFS = 0.63, control =
0.15; P<.001, for difference) and maximum workload (CFS = 0.53,
control = 0.28; P<.002, for difference) and a statistically lower
correlation coefficient for HRAT (CFS = 0.31, control = 0.52; P<.007,
for difference). Thus, in patients with
CFS, the reduction in the percentage of THR achieved was associated with a
reduction in workload capacity.
Those with CFS had a higher
HRrest and a lower HRmax relative to the control subjects (Table 1), and therefore the increase from resting to maximum
heart rate was calculated for the sake of comparison. It was lower in the patients with CFS vs the control subjects
(CFS = 62.5 + 19.0 beats per minute, control = 88.9 + 14.4 beats per minute; P<.001).
In the CFS group, the increase in heart
rate from rest to maximum had a higher positive correlation with the maximum
workload (CFS = 0.68; control = 0.45) and exercise duration (CFS = 0.68;
control = 0.47) (P<.001 for all) compared with the control subjects.
In the second stage of the study,
we examined only those persons who attained a maximal effort as defined by 2
end points: achievement of an RQ of at least 1.0 and an age-predicted THR of at
least 85%. A relatively small
percentage of patients with CFS, 37%, reached both criteria (Table 3). The target
heart rate seemed to be the limiting factor, since only 41% of the patients
achieved an HRmax of at least 85% of the age-predicted THR, whereas 80% of them
reached the anaerobic threshold defined by a minimal RQ of 1.0. Thus, for comparison, we analyzed the
metabolic data of those subjects who had achieved a maximal effort in both
study groups (Table 4).
There was no difference in age
between the 141 patients with CFS and the 158 control subjects (mean + SD years,
CFS = 36.2 + 9.4; control = 35.5 + 9.0) who achieved maximal effort. Those with CFS had a mean illness duration
of 6.8 + 7.0 years.
Discriminant function analysis
was applied to determine the major differences between the exercise response
characteristics of the patients with CFS vs the control subjects who achieved
maximal effort. Table 4 shows that the regression model revealed a large
difference in these characteristics (Wilks λ= 0.10, F = 158.8; P<.001), with a high degree of homogeneity
within the 2 groups. All of the control
subjects complied with the control model profile, and 99.3% of the patients
with CFS complied with the CFS group profile.
Univariate analysis demonstrated that 8 of the 15 exercise profile
measures were reduced in the CFS group relative to the control group and 2 were
increased (HRrest and WAT). Compared
with the initial analysis in the entire study group, the patients with CFS who
achieved maximal responses showed no difference in exercise duration. Most of the exercise parameters found to be
dissimilar between the CFS and control groups were the same in patients who
achieved maximal responses relative to those in the entire cohort of patients
with CFS. Therefore, the exercise
capacity in the patients with CFS who reached their maximal response was still
quite different from that of the control subjects.
Forward stepwise discriminant
function analysis was applied to evaluate the major parameters that determined
the differences between the exercise response characteristic profiles of the
CFS vs the control groups who achieved maximal effort. A strong model was found (Wilks λ = 0.11, F = 184.3), with HRAT being the
primary discriminating variable, followed by WAT and maximal workload per
kilogram of body weight (P<.001 for all). These data show that the parameters differentiating the 2 groups
were the same when analyzing only those in the cohort who achieved maximal
exercise responses.
Exercise capacity was evaluated
in a large cohort of female patients with CFS and compared with that of
sedentary control subjects. The O2max
levels of our control group were consistent with various studies in untrained
women of approximately the same age describing VO2max levels of 30
to 36 mL/kg per minute).31, 32 Our patients with CFS had an average VO2max
just below 20 mL/kg per minute, representing significant impairment relative to
the controls. Comparing the exercise
capacity in our patients with data from other studies shows a functionality
similar to that of elderly healthy controls (60-69 years),31
individuals with chronic heart failure,36
patients with chronic obstructive or restrictive pulmonary disease,37 and
those with skeletal muscle disorder.38 The decrease in physical capacity in
patients with CFS appears to be associated with disease severity and is
consistent with the reduction seen in many other chronic illnesses.
A major criterion for defining
CFS is that patients report a greater than 50% reduction in activity levels
relative to their pre-illness state.2 Maximal workload at exhaustion averaged 53%
of normal in our patients with CFS, which is close to the 50% decrease in
physical capabilities described in the CDC's criteria for CFS.1, 2
Sisto6 and
Riley7
and their colleagues reported only slight reductions in aerobic power on a
graded treadmill test in female patients with CFS. Their patients had an average VO2max of 30.1 mL/kg per
minute and 31.7 mL/kg per minute, respectively, which places them within the
range of sedentary control subjects according to the classification by MacAuley
et al.32 We believe that the failure to assess the
more severely affected patients appears to have led to a disparity in study
conclusions about the exercise capacity in patients with CFS.
In contrast to many investigators5-8 who
have claimed heterogeneity of laboratory and exercise findings when comparing their
results with other CFS studies, our study shows a high degree of homogeneity
within the CFS group in multivariate analysis.
Our statistical homogeneity is an assessment of the differences between
the 2 groups evaluated and does not necessarily reflect clinical
homogeneity. The contradictions between
our study and the heterogeneous findings in other studies may also result from
the array of measures used, different study designs and numbers, and various
interpretations given to the results of those investigations.
Only a small number of patients
with CFS reached both parameters for maximal exercise testing (RQ >1.0 and
HRmax >85% THR). However, when we
analyzed the entire cohort data using only those subjects who fulfilled the
criteria for maximal exercise, we still observed the same differences in
exercise capacity between the CFS group and the control subjects. Multiple regression analysis showed that the
same parameters differentiated between the CFS and control groups as in the
cohort.
The resting heart rate was higher
in patients with CFS, as in other studies.5, 7 Moreover, most of our patients were not able
to achieve their age-predicted THR, a finding that is in agreement with some
previous studies in CFS.8, 10, 17, 20 Although some authors5, 8
believe that the inability to reach the THR indicates incapability to exercise
to full capacity, because of elevated perceptions of exertion or fatigue or
physical deconditioning, a large percentage of our patients who did not reach
their age-predicted THR did reach their RQ of 1.0. Furthermore, Gibson et al17
observed similar heart rates at increasing workloads in CFS and control
subjects, which is more consistent with submaximal exertion than with
deconditioning.5 The increase in HRrest associated with a
lower achieved HRmax suggests that alteration in cardiac function is a primary
factor associated with the reduction in exercise capacity in CFS.
It is a peculiar finding that,
although most of our patients reached the respiratory anaerobic threshold, far
fewer of them also reached their THR.
This would also indicate that suboptimal cardiac function is a major
limiting factor in exercise capacity in patients with CFS. Fischler et al5 use
only the THR criteria to assess whether a patient did or did not perform a
maximal effort. This would suggest that
too great an emphasis is placed on the THR, especially since several studies39-43
suggest autonomic nervous system involvement in CFS that could influence the
chronotropic cardiac systems. It could
be that the increased HRrest and the low HRmax are the result of a disturbed
autonomic system. Possible disturbances
include sympathetic predominance,37, 42
diminished vagal power,41 and
reduced sympathetic responsiveness to stress42 and
exercise.44 Considering that 66% to 90% of patients with
CFS initially develop an acute infectious illness,45
exercise bradycardia might also be related to post-acute viral status, either
as a direct or indirect latent effect, and the possibility that cellular
metabolic pathways are disrupted by the viral presence or by some immunological
process triggered by the acute or persistent infection.46
The exact mechanisms for this are
speculative. It may be that loss of
muscle protein contributes to the perceived muscle weakness.47 Cytokine abnormalities and dysfunction of
the 2-5A Synthetase/RNaseL pathway exert a negative control on protein
synthesis. Both of these anomalies have
been demonstrated in CFS.48-50 In addition, muscle fiber atrophy23-25
and a defect in muscle energy sources need to be explored as there is
disagreement whether patients with CFS show defects in mitochondrial function.14, 23, 24, 26
This study clearly shows that
patients with CFS are limited in their physical capacities. Based on the American Medical Association
Guidelines for Impairment Rating,51 our
55.2% of patients who had a VO2max of less than 20 mL/kg per minute
correspond to class 3-4 on the disability scale, indicating moderate to severe
impairment.51 Regardless of the cause and pathogenesis,
the symptom complex labeled CFS can and does result in prolonged debilitation.3, 4, 51
To our knowledge, this is the
first study on exercise capacity in a large population of patients with CFS and
sedentary control subjects. Physical
capacity based on exercise tolerance is only one of a number of factors that
might be considered in establishing a more global impairment rating. However, we believe it is a strong and
useful tool in assessing a person's physical capability.
Author/Article Information
From the Human Performance
Laboratory and Department of Internal Medicine, Faculty of Physical Education
and Physical Therapy, Vrije Universiteit Brussel, Brussels, Belgium (Drs De
Becker and De Meirleir, Mr Roeykens, and Ms Reynders); and the Collaborative
Pain Research Unit, Department of Biological Sciences, Faculty of Science,
University of Newcastle, Callaghan, New South Wales, Australia (Dr McGregor).
Corresponding author: Pascale De Becker, PhD, Human Performance Laboratory and
Department of Internal Medicine, Faculty of Physical Education and Physical
Therapy, Vrije Universiteit Brussel, LK–Third Floor, Pleinlaan 2, 1050
Brussels, Belgium (e-mail: pdbeck@minf.vub.ac.be).
Accepted
for publication June 7, 2000.
1. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a
comprehensive approach to its definition and study. Ann Intern Med.1994;121:953-959.
2.
Holmes GP, KaplanJE, Gantz NM, et al.
Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;
108:387-389.
3.
Komaroff AL, Fagioli LR, Doolittle TH, et al. Health status in patients with chronic fatigue syndrome and in
general population and disease comparison groups. Am J Med. 1996;101:281-290.
4.
Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W. Functional status in patients with chronic
fatigue syndrome, other fatiguing illnesses, and healthy individuals. Am J Med. 1996;101:364-370.
5.
Fischler B, Dendale P, Michiels V, Cluydts R, Kaufmann L, De Meirleir
K. Physical fatigability and exercise
capacity in the chronic fatigue syndrome: association
with disability, somatisation, and psychopathology. J Psychosom Res. 1997;42:369-378.
6.
Sisto SA, Lamanca J, Cordero DL, et al.
Metabolic and cardiovascular effects of a progressive exercise test in
patients with chronic fatigue syndrome.
Am J Med. 1996; 100:634-640.
7.
Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP. Aerobic work capacity in patients with
chronic fatigue syndrome. BMJ.
1990;301:953-956.
8.
Rowbottom D, Keast D, Pervan Z, Morton A. The physiological response to exercise in chronic fatigue
syndrome. J Chronic Fatigue
Syndrome. 1998;4:33-49.
9.
Kent-Braun JA, Sarma KR, Weiner MW, Massie B, Miller RG. Central basis of muscle fatigue in chronic
fatigue syndrome.
Neurology. 1993;43:125-131.
10.
Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM. Cardiac function at rest and with exercise
in the chronic fatigue syndrome. Chest.
1989;95:779-784.
11.
Noakes TD. Implications of
exercise testing for prediction of athletic performance: a contemporary
perspective. Med Sci Sports Exerc.
1988;20:319-330.
12.
McCully KK, Sisto SA, Natelson BH.
Use of exercise for treatment of chronic fatigue syndrome. Sports Med. 1996;21:35-48.
13.
Arnold DL, Bore PJ, Radda GK, Styles P, Taylor DJ. Excessive intracellular acidosis of skeletal
muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. Lancet. 1984;1:1367-1369.
14.
Barnes PR, Taylor DJ, Kemp GJ, Radda GK. Skeletal muscle bioenergetics in the chronic fatigue
syndrome. J Neurol Neurosurg
Psychiatry. 1993;56:679-683.
15.
Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre characteristics and lactate
responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1998;64:362-367.
16. Wong R,
Lopaschuk G, Zhu G, et al. Skeletal
muscle metabolism in the chronic fatigue syndrome: in vivo assessment by 31P
nuclear magnetic resonance spectroscopy.
Chest. 1992;102:1716-1722.
17.
Gibson H, Carroll N, Clague JE, Edwards RH. Exercise performance and fatiguability in patients with chronic
fatigue syndrome. J Neurol Neurosurg
Psychiatry. 1993;56:993-998.
18.
Lloyd AR, Gandevia SC, Hales JP.
Muscle performance, voluntary activation, twitch properties and
perceived effort in normal subjects and patients with the chronic fatigue syndrome. Brain. 1991;114:85-98.
19.
Lloyd AR, Hales JP, Gandevia SC.
Muscle strength, endurance and recovery in the post-infection fatigue
syndrome. J Neurol Neurosurg
Psychiatry. 1988;51:1316-1322.
20.
Stokes MJ, Cooper RG, Edwards RH.
Normal muscle strength and fatigability in patients with effort
syndromes. BMJ.
1988;297:1014-1017.
21.
Rutherford OM, White PD. Human
quadriceps strength and fatiguability in patients with post viral fatigue. J Neurol Neurosurg Psychiatry.
1991;54:961-964.
22.
McCully KK, Natelson BH, Iotto S, Sisto S, Leigh JS. Reduced oxidative muscle metabolism in
chronic fatigue syndrome.
Muscle Nerve. 1996;19:621-625.
23.
Behan WM, More IA, Behan PO.
Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol (Berl).
1991;83:61-65.
24.
Byrne E, Trounce I. Chronic
fatigue and myalgia syndrome: mitochondrial and glycolytic studies in skeletal
muscle. J Neurol Neurosurg
Psychiatry. 1987;50:743-746.
25.
Gow JW, Behan WM, Simpson K, et al.
Studies on enterovirus in patients with chronic fatigue syndrome. Clin Infect Dis. 1994;18(suppl
1):S126-S129.
26.
Behan WMH, Holt IJ, Kay DH, Moonie P.
In vitro study of muscle aerobic metabolism in chronic fatigue
syndrome. J Chronic Fatigue
Syndrome. 1999;5:3-15.
27.
Jamal GA, Hansen S. Post-viral
fatigue syndrome: evidence for underlying organic disturbance in the muscle
fibre. Eur Neurol. 1989;29:273-276.
28.
Lodi R, Taylor DJ, Radda GK.
Chronic fatigue syndrome and skeletal muscle mitochondrial
function. Muscle Nerve.
1997;20:765-766.
29.
Edwards RH, Gibson H, Clague JE, Helliwell T. Muscle physiology and histopathology in chronic fatigue
syndrome.
In: Bock GR, Whelan J, eds. Chronic Fatigue Syndrome. Chichester,
England: John Wiley & Sons Ltd; 1993:102-131.
30.
Lerner AM, Lawrie C, Dworkin HS.
Repetitively negative changing T waves at 24-h electrocardiographic
monitors in patients with the chronic fatigue syndrome. Chest. 1993;104:1417-1421.
31.
Lewis SF, Haller RG.
Physiologic measurement of exercise and fatigue with special reference
to chronic fatigue syndrome. Rev
Infect Dis. 1991;13(suppl 1):S98-S108.
32.
MacAuley D, McCrum EE, Stott G, et al.
Levels of physical activity, physical fitness and their relationship in
the Northern Ireland Health and Activity Survey. Int J Sports Med. 1998;19:503-511.
33.
Hollmann W, Prinz JP.
Ergospirometry and its history. Sports
Med. 1997;23:93-105.
34.
Davis JA. Direct determination
of aerobic power. In: Maud PJ, Foster
C, eds. Physiological Assessment of Human Fitness. Champaign, Ill: Human
Kinetics; 1995:9-17.
35.
Astrand PO, Rodahl K. Evaluation
of physical performance on the basis of tests.
In: Astrand PO, Rodahl K, eds. Textbook of Work Physiology:
Physiological Bases of Exercise. 3rd ed. New York, NY: McGraw-Hill;
1986:354-387.
36.
Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure:
role of impaired nutritive flow to skeletal muscle. Circulation. 1984;69:1079-1087.
37.
Wehr KL, Johnson RL Jr. Maximal
oxygen consumption in patients with lung disease. J Clin Invest. 1976;58:880-890.
38.
Lewis SF, Haller RG. Skeletal
muscle disorders and associated factors that limit exercise performance. Exerc Sport Sci Rev. 1989;17:67-113.
39.
Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the
chronic fatigue syndrome. JAMA.
1995;274:961-967.
40.
De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne K, Hagers
Y. Autonomic testing in patients with
chronic fatigue syndrome. Am J Med.
1998;105(3A):22S-26S.
41.
Sisto SA, Tapp W, Drastal S, et al.
Vagal tone is reduced during paced breathing in patients with the chronic
fatigue syndrome. Clin Auton Res.
1995;5:139-143.
42.
Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A. Sympathetic overactivity in subjects
complaining of unexplained fatigue. Clin
Sci (Colch). 1994;87:655-661.
43.
Freeman R, Komaroff AL. Does
the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. 1997;102:357-364.
44.
Cordero DL, Sisto SA, Tapp WN, et al.
Decreased vagal power during treadmill walking in patients with chronic
fatigue syndrome. Clin Auton Res.
1996;6:329-333.
45.
Schluederberg A, Straus SE, Peterson P, et al. Chronic fatigue syndrome research: definition and medical
outcome assessment. Ann Intern Med.
1992;117:325-331.
46.
Montague T, Marrie T, Klassen G, et al. Cardiac effects of common viral illnesses. Chest. 1988;94:919-925.
47.
Preedy VR, Smith DG, Salisbury JR, Peters TJ. Biochemical and muscle studies in patients with acute post-viral
fatigue syndrome. J Clin Pathol.
1993;46:722-726.
48.
Lloyd A, Hickie I, Brockman A, Dwyer J, Wakefield D. Cytokine levels in serum and cerebrospinal
fluid in patients with chronic fatigue syndrome and control subjects. J Infect Dis. 1991;164:1023-1024.
49.
Suhadolnik RJ, Reichenbach NL, Hitzges P, et al. Upregulation of the 2-5A Synthetase/RNaseL
antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994;18(suppl
1):S96-S104.
50.
Suhadolnik RJ, Peterson DL, O'Brien K, et al. Biochemical evidence for a novel low molecular weight RNaseL in
chronic fatigue syndrome. J
Interferon Cytokine Res. 1997;17:377-385.
51.
Make B, Jones JF. Impairment of
patients with chronic fatigue syndrome.
J Chronic Fatigue Syndrome. 1997;3:43-55.
© 2000 American Medical Association
Mitochondrial abnormalities in
the postviral fatigue syndrome.
Behan WM,
More IA, Behan PO
Department of Pathology, University of
Glasgow, Scotland.
Acta Neuropathol 1991;83(1):61-5
We have examined the muscle biopsies of 50 patients who had postviral fatigue syndrome (PFS) for from 1 to 17 years. We found mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes. These abnormalities were in obvious contrast to control biopsies, where even mild changes were rarely detected. The findings described here provide the first evidence that PFS may be due to a mitochondrial disorder precipitated by a virus infection.
PMID:
1792865, UI: 92170301
Central basis of muscle
fatigue in chronic fatigue syndrome.
Kent-Braun
JA, Sharma KR, Weiner MW, Massie B, Miller RG
Department
of Neurology, University of California, San Francisco.
Neurology 1993
Jan;43(1):125-31
We studied whether muscle fatigue, metabolism, or activation are abnormal in the chronic fatigue syndrome (CFS). Subjects performed both an intermittent submaximal and a sustained maximal voluntary isometric exercise protocol of the tibialis anterior muscle. The extent of fatigue, metabolic response, and changes in both M-wave amplitude and twitch tension during exercise were similar in patients and controls. The response to systemic exercise was also normal in the patients. However, voluntary activation of the tibialis was significantly lower in the patients during maximal sustained exercise. The results indicate that patients with CFS have (1) normal fatigability and metabolism at both the intracellular and systemic levels, (2) normal muscle membrane function and excitation-contraction coupling, and (3) an inability to fully activate skeletal muscle during intense, sustained exercise. This failure of activation was well in excess of that found in controls, suggesting an important central component of muscle fatigue in CFS.
PMID: 8423875, UI: 93140980
Impaired oxygen delivery to
muscle in chronic fatigue syndrome.
McCully KK,
Natelson BH
Department of Medicine, Medical College
of Pennsylvania and Hahnemann University, Philadelphia, PA 19129, USA.
kmccully@coe.uga.edu
Clin Sci (Colch) 1999 Nov;97(5):603-8
The purpose
of this study was to determine if chronic fatigue syndrome (CFS) is associated
with reduced oxygen delivery to muscles.
Patients with CFS according to CDC (Center for Disease Control) criteria
(n=20) were compared with normal sedentary subjects (n=12). Muscle oxygen delivery was measured as the
rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the
medial gastrocnemius muscle using continuous-wavelength near-IR
spectroscopy. Phosphocreatine
resynthesis was measured simultaneously using (31)P magnetic resonance
spectroscopy. The time constant of
oxygen delivery was significantly reduced in CFS patients after exercise
(46.5+/-16 s; mean+/-S.D.) compared with that in controls (29.4+/-6.9 s). The time constant of oxygen delivery was
also reduced (20.0+/-12 s) compared with controls (12.0+/-2.8 s) after cuff
ischaemia. Oxidative metabolism was
also reduced by 20% in CFS patients, and a significant correlation was found
between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced
in CFS patients compared with that in sedentary controls. This result is
consistent with previous studies showing abnormal autonomic control of blood
flow. Reduced oxidative delivery in CFS
patients could be specifically related to CFS, or could be a non-specific
effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could
result in reduced oxidative metabolism and muscle fatigue, further studies will
be needed to address this issue.
PMID: 10545311
Skeletal muscle metabolism
in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic
resonance spectroscopy.
Wong R,
Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R,
Montague T
Department of Medicine, University of Alberta,
Edmonton, Canada.
Chest 1992 Dec;102(6):1716-22
BACKGROUND:
Previous study of patients with chronic fatigue syndrome (CFS) has demonstrated
a markedly reduced dynamic exercise capacity, not limited by cardiac performance
and in the absence of clinical neuromuscular dysfunction, suggesting the
possibility of a subclinical defect of skeletal muscle. METHODS: The in vivo
metabolism of the gastrocnemius muscles of 22 CFS patients and 21 normal
control subjects was compared during rest, graded dynamic exercise to
exhaustion and recovery, using 31P nuclear magnetic resonance (NMR)
spectroscopy to reflect minute-to-minute intracellular high-energy phosphate
metabolism. RESULTS: Duration of exercise was markedly shorter in the CFS
patients (8.1 +/- 2.8 min) compared with the normal subjects (11.3 +/- 4.3 min)
(p = 0.005). There were large changes in phosphocreatine (PCr), inorganic
phosphate (Pi), and pH from rest to clinical fatigue in all subjects,
reflecting the high intensity of the exercise. The temporal metabolic patterns
were qualitatively similar in the CFS patients and normal subjects. There were
early and continuous changes in PCr and Pi that peaked at the point of fatigue
and rapidly reversed after exercise. In contrast, pH was relatively static in
early exercise, not declining noticeably until 50 percent of total exercise
duration was achieved, and reaching a nadir at 2 min postexercise, before
rapidly reversing. There were no differences in pH at rest (7.08 +/- 0.04 vs
7.10 +/- 0.04), exhaustion (6.85 +/- 0.17 vs 6.76 +/- 0.17) or early (6.64 +/-
0.25 vs 6.56 +/- 0.24) or late recovery (7.09 +/- 0.04 vs 7.10 +/- 0.05), CFS
patients vs normal subjects, respectively (NS). Neither were there intergroup
differences (NS) in PCr or Pi. Although, quantitatively, the changes in PCr,
Pi, and pH were marked and similar in both groups from rest to exhaustion, the
changes all occurred much more rapidly in the CFS patients. Moreover, adenosine
triphosphate (ATP) was significantly (p = 0.007) less at exhaustion in the CFS
group. CONCLUSIONS: Patients with CFS and normal control subjects have similar
skeletal muscle metabolic patterns during dynamic exercise and reach similar
clinical and metabolic end points. However, CFS patients reach exhaustion much
more rapidly than normal subjects, at which point they also have relatively
reduced intracellular concentrations of ATP. These data suggest a defect of
oxidative metabolism with a resultant acceleration of glycolysis in the working
skeletal muscles of CFS patients. This metabolic defect may contribute to the
reduced physical endurance of CFS patients. Its etiology is unknown. Whether
CFS patients' overwhelming tiredness at rest has a similar metabolic
pathophysiology or etiology also remains unknown.
PMID:
1446478, UI: 93076532
Specific oxidative
alterations in vastus lateralis muscle of patients with the diagnosis of
chronic fatigue syndrome
Stefania Fulle (a), Patrizia Mecocci (b),
Giorgio Fano (c), Iacopo Vecchiet (d), Alba Vecchini (e), Delia Racciotti (d),
Antonio Cherubini (b), Eligio Pizzigallo (d), Leonardo Vecchiet (c), Umberto
Senin (b) and M. Flint Beal (f).
Address correspondence to: Dr. M. Flint Beal, Chairman, Neurology
Department, New York Hospital-Cornell Medical Center, 525 East 68th Street,
New York, NY 10021, USA; Tel: (212) 746-6575; Fax: (212) 746-8532;
email: fbeal@mail.med.cornell.edu
Free
Radical Biology and Medicine Dec 15,
2000, Vol. 29, No. 12, 1252-59
Chronic fatigue syndrome
(CFS) is a poorly understood disease characterized by mental and physical
fatigue, most often observed in young white females. Muscle pain at rest, exacerbated by exercise, is a common
symptom. Although a specific defect in muscle metabolism has not been clearly
defined, yet several studies report altered oxidative metabolism. In this study, we detected oxidative damage
to DNA and lipids in muscle specimens of CFS patients as compared to
age-matched controls, as well as increased activity of the antioxidant enzymes
catalase, glutathione peroxidase, and transferase, and increases in total
glutathione plasma levels. From these
results we hypothesize that in CFS there is oxidative stress in muscle, which
results in an increase in antioxidant defenses. Furthermore, in muscle membranes, fluidity and fatty acid
composition are significantly different in specimens from CFS patients as
compared to controls and to patients suffering from fibromyalgia. These data support an organic origin of CFS,
in which muscle suffers oxidative damage.
Reduced oxidative muscle metabolism in chronic
fatigue syndrome.
McCully KK,
Natelson BH, Iotti S, Sisto S, Leigh JS Jr
Department of Medicine, Medical College of Pennsylvania, Philadelphia
19131, USA.
Muscle Nerve 1996
May;19(5):621-5
The
purpose of this study was to determine if chronic fatigue syndrome (CSF) is
characterized by abnormalities in oxidative muscle metabolism. Patients with
CFS according to Centers for Disease Control (CDC) criteria (n = 22) were
compared to normal sedentary subjects (n = 15). CFS patients were also tested
before and 2 days after a maximal treadmill test. Muscle oxidative capacity was
measured as the maximal rate of postexercise phosphocreatine (PCr) resynthesis
using the ADP model (Vmax) in the calf muscles using 31P magnetic resonance
spectroscopy. Vmax was significantly reduced in CFS patients (39.6 +/- 2.8
mmol/L/min, mean +/- SE) compared to controls (53.8 +/- 2.8 mmol/L/min). Two
days postexercise there was no change in resting inorganic phosphate (Pi)/PCr
or Vmax in the CFS patients (n = 14). In conclusion, oxidative metabolism is
reduced in CFS patients compared to sedentary controls. In addition, a single
bout of strenuous exercise did not cause a further reduction in oxidative
metabolism, or alter resting Pi/PCr ratios.
PMID:
8618560, UI: 96189166
Russell J M Lane,a Michael C Barrett,b
David Woodrow,b Jill Moss,b
Robert Fletcher,b Leonard C Archardc
a Division
of Neuroscience and Psychological Medicine, b Division
of Diagnostic and Investigative Sciences, c Division
of Biochemical Sciences, Imperial College School of Medicine, Charing Cross
Hospital, London, UK
J Neurol Neurosurg Psychiatry 1998;64:362-367
OBJECTIVESTo
examine the proportions of type 1 and type 2 muscle fibres and the degree
of muscle fibre atrophy and hypertrophy in patients with chronic
fatigue syndrome in relation to lactate responses to exercise, and
to determine to what extent any abnormalities found might be due to
inactivity.
METHODSQuadriceps
needle muscle biopsies were obtained from 105 patients with chronic
fatigue syndrome and the proportions of type 1 and
2 fibres and fibre atrophy and hypertrophy factors were determined
from histochemical preparations, using a semiautomated image
analysis system. Forty one randomly
selected biopsies were also examined by electron microscopy. Lactate responses to exercise were
measured in the subanaerobic threshold exercise test (SATET).
RESULTSInactivity
would be expected to result in a shift to type 2 fibre predominance and
fibre atrophy, but type 1 predominance (23%) was more common
than type 2 predominance (3%), and fibre atrophy was found in
only 10.4% of cases. Patients with
increased lactate responses to exercise did have significantly fewer
type 1 muscle fibres (p<0.043 males, p<0.0003 females),
but there was no evidence that this group was less active than the
patients with normal lactate responses. No significant ultrastructural abnormalities were
found.
CONCLUSIONMuscle
histometry in patients with chronic fatigue syndrome generally did not show the
changes expected as a result of inactivity. However, patients with abnormal lactate responses to
exercise had a significantly lower proportion of mitochondria rich
type 1 muscle fibres.