is Chronic Fatigue Syndrome - what else is it called?
Doctors regularly see patients
whose main symptom is that of severe fatigue often associated
with other symptoms, but not conforming to a clear cut medical
diagnosis. A variety of terms have been devised to describe
these conditions such as "irritable bowel syndrome"
and "neurasthenia". Recently the terms "myalgic
encephalomyelitis" ("ME") and "post viral
fatigue syndrome" have been introduced. However, neither
of these are particularly satisfying terms because encephalomyelitis
refers to a distinct neuropathological process which is not
found, and post viral fatigue syndrome implies that all cases
occur after a viral illness which is not the case. Prospective
controlled studies from the Institute of Psychiatry have shown
that although most sufferers seen in our specialist clinic
remember a viral infection as the trigger for their illness,
common viral infections are not associated with the illness.
An international consensus
has therefore been reached that the term "chronic fatigue
syndrome" (CFS) a label which is both short and accurate
should be used.
Symptoms and treatments
There are no diagnostic signs
or symptoms of CFS. A variety of symptoms, such as post exertional
fatigue or myalgia (muscle pain); difficulties in concentration
and short term memory; subjective changes in temperature and
many others have been reported but none are diagnostic. The
diagnosis is therefore made in someone with excessive physical
and mental fatigue, brought on by physical or mental effort,
and with associated functional disability, for whom a conventional
biomedical explanation cannot be found.
No specific treatment exists,
although a variety of agents have been tried. Various antiviral
drugs, or agents acting on the immune system, have been tested,
but none can be recommended at present. Nutritional supplements
are popular, and so long as they are cheap and free from side
effects, may have a place.
Antidepressants are known
to be successful in the related conditions of fibromyalgia,
and should be used in patients with depressive features. It
is also possible that antidepressants have a direct effect
on fatigue and myalgia independent of mood disorder, but this
is not yet established. The Institute of Psychiatry is participating
in a current clinical trial to assess this further. The mainstay
of treatment, however, remains rehabilitation. Thus researchers
have developed a rehabilitation package using cognitive behaviour
therapy to combat both physical deconditioning and psychological
problems. They believe that the counselling previously recommended
of rest is of little value, and may indeed prolong the symptoms
of fatigue, pain and depression.
Researchers are involved in
research into the prevalence of CFS in the community. Results
show that whereas fatigue is very common, few people are labelled
as having "ME" or "post viral fatigue".
Both groups have also confirmed that the stereotype of "Yuppie
flu" is a myth, and that there is no excess of these
illnesses in upper social classes.
Causes of the illness
The cause of chronic fatigue
syndrome is unknown and is being investigated by researchers
at the Institute of Psychiatry. For example, they are investigating
whether there are immunological or virological explanations
of CFS. It has been discovered that some patients show immunological
abnormalities, such as high levels of circulating immune complexes,
altered serum immunoglobulins and low levels of natural killer
cells, but at present these findings are inconclusive.
The role of infection in CFS
is also unclear. Certainly, fatigue syndromes do occur after
many infections, both viral (e.g. infectious mononucleosis
or influenza) and bacterial (e.g. brucellosis). However these
syndromes may not be a major risk factor for abnormal fatigue
of longer that six months duration. At present only Epstein
Barr virus (EBV), the virus that causes glandular fever, is
known to be associated with chronic fatigue syndrome. Research
continues on other agents, but most studies have draw a blank.
There is a close association with psychological disorder,
with rates in excess of what could be expected as a reaction
to physical illness. Up to 70% of those seen in primary or
specialist care fulfil criteria for psychiatric disorders,
particularly depression, anxiety and somatisation disorders.
Not surprisingly some neurobiological and neuropsychological
abnormalities have been identified, both by studies here and
elsewhere. Whereas we have been unable to replicate some findings
of abnormalities on structural neuroimaging, we have reported
the finding of hypocortisolaemia and an underactive hypothalamo-pituitary
axis together with preliminary evidence of increased central
5HT neurotransmission in some CFS patients. The significance
of these observations remains unclear.
Certain factors are known
to increase the risk of developing CFS. For example, it is
more common in patients who have had previous psychiatric
illness, particularly when associated with an infective illness.
In addition, certain infections may also themselves predispose
to CFS, in particular glandular fever, encephalitic illnesses,
and also other causes of central nervous damage. Finally,
lack of physical fitness, particularly in previously fit people
forced into inactivity may play a role in perpetuating CFS.
Psychiatric illness and
chronic fatigue syndrome
There is no doubt that the
symptoms of CFS overlap with those of severe psychiatric disorders.
Nearly all depressed patients report substantial fatigue,
and for some it is the most distressing part of the illness.
However, the precise role of psychiatric disorder in CFS is
not yet clear. Psychiatric illness is occasionally a consequence
of physical illness, but this does not explain the higher
rates of psychiatric disorder found in CFS compared with other
chronic illness. More work on possible brain dysfunctioning
is being carried out at the Institute of Psychiatry to explore
these links further.
What is very clear is that
sufferers make dramatic alterations in lifestyle, resulting
in frequent physical deconditioning. Despite these observations,
many hold extremely strong views that the illness has a solely
organic basis. Suggestions that psychological factors may
be relevant, or even a psychiatric referral appropriate, will
rarely be met with approval. We have carried out some sociological
and historical research on the cultural reasons underlying
CFS. We have shown how such factors as the perceived stigma
of psychological illness, current views on viruses and immunity
in disease, the role of physical attributions in protecting
self esteem, and the role of social and personality factors
in vulnerability to illness, are all relevant. Overall, the
intense political controversy and passions aroused by CFS
relate to the issue of what is, and what is not, a legitimate
illness in current society.
The Institute of Psychiatry
has a unique role to play in investigating these disabling
conditions. We have published studies on the neuroendocrinology,
psychology, epidemiology, physiology, history and treatment
of this condition. We have pioneered the development of an
effective package based on the principles of cognitive behaviour
therapy. We recently published the results of a 5 year follow
up study of patients treated in an open fashion with this
new approach, and showed that treatment gains were maintained
over the period. As a result we undertook a formal randomised
controlled trial, comparing the new technique with relaxation
therapy. This was successful. Further trials are now underway
looking at the new treatment in primary care, and also looking
at the effects of a self help package. Finally, we are participating
in a randomised controlled trial of a selective serotonin
reuptake inhibitor, but focusing on non-depressed patients.
Studies of neuropsychology have been undertaken, and it is
hoped that a new study using neuroimaging will start soon.
Research has led to substantial
advances in our understanding of the epidemiology, aetiology
and mechanisms underlying CFS. Finally, no one should now
say "CFS - there is nothing you can do about it".
Neurobiology of Chronic
The Chronic Fatigue Syndrome
Research and Treatment Unit has now been running for nearly
10 years, and has seen around 1000 patients. During that time,
we have made great inroads into defining the epidemiology
of the illness (i.e. how much of it there is, who gets it,
how long they have it for and what happens to them), unravelling
the psychological components of the illness, and devising
new and effective treatment programmes for patients. I joined
the unit in 1995, and have been working since then on attempting
to define the neurobiological components of the illness, and
how they might interact with the psychological.
Background to the illness
Patients complaining of fatigue
are common: 20-50% of the population report suffering from
fatigue, while 10% of GP attenders report fatigue for 6 months
or more. A smaller group can be shown to have significant
disability resulting from their fatigue. In recent years,
this severe end of the spectrum of chronic fatigue has been
operationally defined as Chronic Fatigue Syndrome (CFS). The
definition is of medically unexplained fatigue of at least
6 months duration that is of new onset, is not a result of
ongoing exertion, is not substantially alleviated by rest,
and leads to a substantial reduction in previous levels of
activity. In addition, 4 or more of the following symptoms
must be present: subjective memory impairment; sore throat;
tender lymph nodes; muscle pain; joint pain; headache; unrefreshing
sleep; and post exertional malaise delayed by 24 hours. Exclusion
criteria for CFS include the presence of an underlying disease
likely to cause fatigue, severe psychiatric illness (psychosis,
melancholic or bipolar depression, dementia, eating disorder,
substance misuse) or severe obesity. Myalgic Encephalomyelitis
(ME) is a frequently used, though medically incorrect, popular
term for this condition.
Recent estimates at the prevalence
of CFS in the community vary from 0.5% to 1.5%. The only significant
demographic difference is that of gender with the relative
risk for women varying between 1.3 and 1.7. While those seen
in specialist clinics are more often from higher social classes,
this is likely to be a referral bias, since population surveys
do not find that CFS is less likely to occur in groups of
lower socio-economic status or in ethnic minorities.
Although it is unlikely that
CFS is a single illness, efforts to define valid subgroups
have not yet been fruitful. Differences do exist between the
minority of cases with long illness histories, severe disability
and multiple symptoms, who show overlap with the concept of
somatisation disorder, and the larger group with less disability,
fewer symptoms and shorter illness durations, who have a better
prognosis. We take the view that CFS is an illness in which
there are many different causal factors both between different
patients and within individual patients. The aetiology represents
an interaction of the biological, psychological and social
Research into the neurobiology
Genetics: Although systematic
family studies have not been undertaken, recent twin studies
from others at the Institute of Psychiatry do suggest a genetic
propensity to suffer from chronic fatigue.
Viruses: In the clinic, the
majority of patients with CFS date the onset of their symptoms
to a viral infection of some sort. Many positive findings
of 'the CFS virus' were published; however, even ignoring
the major methodological problems in many studies, no findings
of an association between CFS and the persistence of a certain
virus have been replicated in different populations or by
different research groups. We have recently begun testing
again after reports of high rates of newly discovered viruses,
and again have no evidence for specific viral persistence
in our patients. We have, however, published evidence that
certain severe viral infections (e.g. glandular fever or meningitis)
are 'triggers' for CFS.
axis: The hypothalamo-pituitary-adrenal (HPA) axis is the
primary long-term mediator of the body's stress response.
Initial interest in this axis was generated by the observation
that Addison's disease (underactive adrenal glands) is characterised
by many CFS-like symptoms. Recent research from our own group
has revealed evidence of mildly reduced adrenal production
of cortisol, both basal and after stimulation. We recently
reviewed the literature and found support for this, although
not all studies agree. The reason why cortisol levels are
lowered is also unclear: many factors influence cortisol secretion,
including changes in sleep, activity and appetite. For example,
night shift working can produce similar changes to the HPA
axis. It is probable that, once again, the HPA axis changes
in CFS are due to several factors, and may be subtly different
depending the exact factors present in each patient (e.g.
sleep, physical activity, presence of depression, drugs taken,
or circadian rhythm changes).
Other neuroendocrine changes: There were early reports of
impaired growth hormone (GH) function in CFS. However, we
recently undertook a thorough investigation of the GH-IGF
axis in CFS, using basal IGF-1, IGF-2, IGFBP-1, IGFBP-2 &
IGFBP-3 levels, 24-hour urinary GH, GHRH challenge testing
and insulin stress testing. We found no impairment in GH-IGF
function, and concluded that the axis was normal in CFS.
Immunology: Although there
are several reports of alterations in immune parameters, most
frequently of a mild immune activation, these are inconsistent.
At present it is impossible to determine the significance
of the observed changes in immunological status in CFS. Our
own studies suggest no link between any immune changes and
clinical symptoms or outcome [.
Neurochemistry: Changes in
central serotonin (5-HT) levels have been hypothesised as
a possible physiological mechanism underlying central fatigue.
We have measured brain 5-HT function using the neuropharmacological
challenge paradigm. For example, the prolactin response to
a standardised dose of d-fenfluramine, a drug that selectively
causes release of 5-HT in the brain, gives an indication of
the responsiveness of brain 5-HT pathways. We found that CFS
subjects show a higher prolactin response than controls, in
contrast to depressed patients who have a reduced response
, a finding confirmed by others. We are now using positron
emission tomography (PET) to measure directly 5-HT receptors
Muscle: Complaints of muscle
pain or fatigability are common in CFS. However, most studies
of neurophysiological function have been normal, particularly
once the secondary effects of inactivity are taken into account.
Autonomic nervous system:
Several studies have investigated the possible role of the
autonomic nervous system in CFS. Most striking has been studies
reporting an increased rate of neurally mediated hypotension,
while there is also some evidence suggesting sympathetic overactivity
and/or parasympathetic underactivity. However, it remains
unclear whether or not these are causal factors in CFS, since
both anxiety and prolonged inactivity are associated with
Neuroimaging: There have been
several recent studies using neuroimaging techniques such
as SPET to study cerebral blood flow in CFS. Whilst a number
of abnormalities have been found, including lowered perfusion
of the brain stem and frontal lobes, many investigators have
failed to replicate these findings. A review by Professor
David of the Unit noted that one can often diagnose alternative
illnesses or organic brain diseases in those showing abnormalities.
Furthermore, depression or anxiety can be associated with
similar changes in cerebral blood flow and many studies have
not been rigorous enough in separating out these confounding
influences. Nevertheless, neuroimaging remains a useful tool
for the future. We are starting to undertake studies using
functional magnetic resonance to identify the neural correlates
of the subjective experience of fatigue; these may enhance
our understanding of the brain mechanisms underlying the sense
of effort, and possible disturbances in CFS.
Interaction with Psychological
and Social Factors
It is clear that, as in most
illnesses, there is an interaction of any biological processes
with psychological and social ones. Briefly, any coherent
explanation of CFS must try to integrate these findings. This
is beyond the scope of this brief article, but examples of
potential interactions coming out of our research include:
a) Life Events: Adverse life events are related to the development
of acute fatigue, and to the subsequent chronicity of this
fatigue, while positive life events may be protective. This
may link with the neurobiological research on the stress axis
b) Other precipitants to CFS: These include major surgery,
overtraining, cancer treatment or drugs (e.g. interferon).
We are currently investigating these specific conditions,
but suggest that they all share the interaction of psychological
and physiological factors in producing the final clinical
c) Psychological Disorder: The relationship between psychiatric
disorder and CFS remains controversial, but there is no doubt
that such a relationship exists: between one half and two
thirds of most clinical samples fulfil criteria for psychiatric
disorder as well as CFS. The commonest psychiatric disorder
reported in studies of CFS is depression (perhaps because
of the overlap of the operationalised criteria). However,
in some respects CFS shares more similarities with anxiety
than depression - particularly in terms of neuroendocrine
dysfunction, the role of fear and avoidance behaviour, and
d) Neuropsychological function: Most patients attending clinics
with CFS experience marked difficulties with various neuropsychological
functions, such as memory, attention and concentration. Whilst
objective tests have failed to document conventional cognitive
impairments in keeping with the severity of subjective complaints,
there is evidence for some disturbance of complex information
processing and efficiency. It is plausible that sufferers
find that everyday tasks require increased cognitive resources;
although they are able to perform reasonably well on such
tasks, it is at the price of increased mental effort. Once
again, we are hoping to use neuroimaging to attempt to discern
any underlying neural changes, a process begun by others.
e) Cognitive-behavioural factors: The cognitive behavioural
model operates independently of the initial precipitants of
fatigue, but separates out the components of CFS into those
acting as risk factors, triggers and perpetuating factors.
Thus, an initial physiological trigger for fatigue (a severe
virus, or those mentioned in (b) above) can be perpetuated
by these factors, including: physiological and psychological
effects of inactivity; inconsistent activity patterns; illness
beliefs; and symptom focusing. Social factors may act similarly
Implications for Treatment
The mainstays of treatment
at present are based on Graded Exercise and Cognitive Behavioural
Therapy, for which there is a good evidence base in the literature.
In keeping with our integrative approach, we are currently
study possible biological changes consequent to these therapies.
Studies of antidepressants
in CFS have been few, and the results generally disappointing.
Given our findings on opposing changes in 5-HT systems between
depression and CFS, at least in those CFS patients who are
not also depressed, these results may not be that surprising.
More positively, there is preliminary evidence of a modest
clinical response to the newer antidepressant moclobemide.
Following directly on from
our findings of reduced cortisol levels in CFS, our group
undertook a randomised, placebo-controlled trial of very small
doses (5-10 mg daily for one month) of hydrocortisone (identical
to cortisol) in an attempt to supplement the reduced endogenous
production. This produced large reductions in fatigue in 28%
of patients, compared to 9% in those receiving placebo. Importantly,
this regime did not impair the ability of the adrenal glands
to continue to produce cortisol, a risk with higher doses
of hydrocortisone. Furthermore, those who responded to treatment
reported reduced disability ratings, and endocrine testing
showed a reversal of the pre-treatment deficient cortisol
response to CRH challenge  Potential side effects and the
lack of follow up data beyond one month preclude such strategies
as routine treatments at present, but suggest that low cortisol
levels and HPA axis disturbances may be one significant perpetuating
factor in CFS.
CFS is not due to a single
cause. As outlined above, the fullest understanding of CFS
at the present time involves using a multi dimensional approach,
in which due attention is given to both physical and psychological
factors, and to their interaction. As with other multifactorial
conditions, it is important to consider the roles of predisposing,
precipitating and perpetuating factors from a biopsychosocial
perspective. For now, the most effective interventions are
aimed at possible perpetuating factors. As more is understood
in the future, it is possible that there will be greater potential
for targeting risk factors, the prevention of CFS after identified
triggers, or the modification of the biological processes
underlying fatigue. This remains a serious challenge for the