ARTICLE IN PRESS
Prostaglandins, Leukotrienes and Essential Fatty Acids 71 (2004) 181–183
In vivo magnetic resonance spectroscopy in chronic fatigue
syndrome$
A. Chaudhuri*, P.O. Behan
Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, University of Glasgow, 1345 Govan Road,
Glasgow G51 4TF, UK
Received 19 December 2003
Abstract
The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and
muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and
brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients
indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased
peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation
for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a
research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS
has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.
r 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Chronic fatigue syndrome (CFS) is a potentially
disabling disorder characterised by otherwise unexplained, overwhelming persistent or relapsing fatigue
of new onset in variable combination with postexertional malaise, unrefreshing sleep, self-reported
impairment in short-term memory, headache, muscle
and joint pain [1]. CFS is usually, but not always,
associated with a preceding viral infection (post-viral
fatigue syndrome) and affects all age groups, usually
affecting more women than men [2]. There is no specific
or sensitive diagnostic test for CFS and the condition is
diagnosed after exclusion of other known medical and
major psychiatric disorders. CFS lacks specific and
effective therapy. Because of its chronicity and consequent disability in adults, a diagnosis of CFS has
significant socio-economic impact [2].
Magnetic resonance spectroscopy (MRS) is a noninvasive imaging technique that may be applied to study
$
Presented at the ‘‘Brain Phospholipids’’ Conference, Aviemore,
Scotland, September 2003, held to honour Dr. David Horrobin.
*Corresponding author. Tel.: +44-141-201-2492; fax: +44-141-2012993.
E-mail address: [email protected] (A. Chaudhuri).
0952-3278/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.plefa.2004.03.009
metabolic changes of muscles and brain in vivo. 31P
MRS has been used to study exercising muscles of CFS
patients. More recently, 1H MRS of regional brain areas
of interest has been carefully studied in well-defined CFS
patients. This article will briefly review the MR spectroscopic data in CFS and the implications of these
observations with respect to the disease mechanism
and possible therapy.
2. MRS of skeletal muscles in CFS
Earlier studies of MRS in patients with CFS were
concentrated on the skeletal muscles because of the view
taken by the researchers that pain and fatigue in CFS
were largely myopathic. 31P MRS provides an excellent
method for continuous, in vivo, monitoring of intracellular energy metabolism in skeletal muscles. MRS
studies of skeletal muscles have shown a significant
reduction in the exercise capacity in CFS, accompanied
by excessively early intracellular acidification [3–7]. The
first positive report [3] of a single case of CFS was
followed by work from the same group showing similar
features in five of six cases [4] and then 12 out of 46
patients who had abnormally reduced phosphocreatine
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(PCr): adenosine triphosphate (ATP) ratios and higher
adenosine diphosphate (ADP) on exercise in the
31
P MRS of their skeletal muscles [5]. Other workers
have also confirmed that patients with CFS have
relatively reduced concentrations of ATP in the exercising muscles. A significant reduction in aerobic metabolism was noted in muscle PCr recovery during exercise
[6]. Another study compared 22 CFS patients with
normal sedentary subjects before and for 2 days after a
maximal treadmill test [7]. Muscle oxidative capacity
was measured as the maximal rate of post-exercise PCr
resynthesis in the calf muscles using 31P MRS. The
oxidative capacity (maximal rate of ATP synthesis) was
significantly reduced in CFS patients as opposed to
controls. No further changes, however, were seen in the
post-exercise period [7]. The metabolic abnormality
common to these observations is a reduced availability
of muscle ATP probably because of an accelerated rate
of breakdown to ADP.
A subgroup of CFS patients has been consistently
shown to produce excess lactate after subanaerobic
exercises [8]. Data from MRS of muscles indicate that
CFS patients who produce abnormal lactate response to
subanaerobic exercise may have a metabolic component
to their muscle fatigue [9].
ity. Whether referenced to water or other metabolites,
the peak of the choline-containing compounds in the
basal ganglia showed significant increases in the CFS
group as compared to the healthy controls. The
statistical strength of this association was extremely
high (Po0:001) [14]. In the only 1H MRS study of
paediatric CFS (ages 11–13 years), a remarkable
elevation of Cho:Cr ratio was similarly observed in the
basal ganglia [15]. None of the studied cases had focal
structural abnormalities of brain in the MRI.
1
H MRS is a relatively new tool for imaging metabolic
brain function. NAA levels broadly correlate with the
regional neuronal function while Cr is generally
considered to be an unvarying metabolic marker, the
reason for its use as a reference in the 1H MRS. Cho
peak is largely derived from the cell membrane
phospholipids (phosphatidylcholine and phosphoglycerylcholine) by phospholipases in an ATP-driven enzymatic reaction. In the absence of inflammation and
tissue necrosis, elevated Cho resonance is considered to
be a marker of increased cell membrane turnover
associated with gliosis [16] or altered intramembrane
signalling [17].
5. Discussion and conclusions
3. MRS in syndrome X and CFS
Cardiac syndrome X is characterised by anginal chest
pain and normal coronary angiogram. A substantial
proportion of patients with cardiac syndrome X develop
fatigue, muscle pain and exercise intolerance in longitudinal follow up, similar to the symptoms experienced
by patients with CFS [10]. Like CFS, cardiac syndrome
X is more common in women than men. A 31P MRS
study of the cardiac muscles demonstrated an abnormal
exercise-induced reduction in the myocardial PCr:ATP
ratio in 20% of female patients (seven out of 35) with
cardiac syndrome X [11]. A reduced level of ATP in the
cardiomyocytes is considered to be the likely explanation for the observed metabolic defect in patients with
angiogram-negative chest pain syndrome.
4. MRS of regional brain areas in CFS
1
H MRS in seven CFS patients was reported to show
reduced levels of N-acetyl aspartate (NAA) in the right
hippocampus [12]. In a recent study of 1H MRS in eight
CFS patients without psychiatric symptoms, a relative
increase in choline (Cho): creatine (Cr) ratio was
observed in the occipital cortex with high statistical
significance [13]. Similarly, increased choline resonance
was also observed in the 1H MRS of left-basal ganglia in
eight adult CFS patients without psychiatric co-morbid-
Muscle MRS studies in CFS seem to indicate that
there may be a reduced availability of ATP in the
excitable tissues, either because of an increased rate of
ATP breakdown or a limited rate of ATP re-synthesis.
Increased utilisation of ATP may occur due to the
activated phospholipases and increased Cho resonance
in the cerebral 1H MRS may reflect this process. All
neurotransmitters and growth factors activate one or
more phospholipases. Cytokines also activate membrane phosphlipases and it is not a surprise that
symptoms of fatigue comparable to CFS are experienced by patients with a wide variety of infective and
inflammatory disorders. There is further evidence that a
number of viruses can affect phospholipase functions
directly. Viral membrane glycoprotein and viroporin
molecules induce changes in the host cell membrane
permeability, leading to the activation of phospholipases
with consequent release of a number of phospholipid
moieties including choline [18].
Phospholipase signal transduction pathways are
complex and can affect a range of membrane functions
and receptor sensitivity of the cells. During the process
of phospholipid signal transduction mediated by the
phospholipases, many important molecules are released
with diverse effects on cell function [19]. It has been
previously proposed that symptoms of CFS may be
related to altered ion channel function [20] and 1H MRS
studies suggest that neuronal phospholipid metabolism
may play an important role in CFS. At the level of
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muscles, reduced availability of ATP is likely to impair
aerobic metabolism and limit exercise tolerance. This is
supported by an abnormal lactate response to exercise
reflecting an impaired energy metabolism in muscles in a
proportion of CFS patients [8]. Abnormal thallium
cardiac perfusion scans in CFS patients suggest possible
myocardial metabolic changes similar to cardiac syndrome X [21].
Increased choline resonance in the 1H MRS of basal
ganglia and occipital cortex may support a clinical
diagnosis of CFS and differentiate it from other
disorders of chronic fatigue. However, it is not only
necessary to do larger studies but also to compare
results with patients with depression before 1H MRS can
be advocated for clinical use in CFS patients. Muscle 31P
MRS and regional brain 1H MRS may also have the
potential to be used as observer-independent outcome
measures in the interventional studies of CFS. If
oxidative stress is considered to be the final common
pathway for increased phospholipase activity and
reduced ATP leading to fatigue, then it would be
rational to use therapeutic stregies to contain this
process. Anti-oxidants, including highly unsaturated
fatty acids (HUFA), are options that may be used with
good reason in CFS until more specific knowledge about
the neurobiology and cellular mechanism of this
complex disorder comes to light. The usefulness of any
biological model depends on whether it leads to an
effective treatment or not. It is necessary to consider
well-designed therapeutic trials in CFS with objective
markers like 1H MRS of selected brain areas.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Acknowledgements
We are grateful to the David & Frederick Barclay
Foundation for generously supporting research in
fatiguing neurological disorders.
[17]
[18]
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