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Lucy Belin got to the point where her skin was so sensitive she couldn’t
wear make-up, jewellery or even her glasses. Brown rice was the most she
could stomach, and a good day was one when she had enough energy to stay
out of bed for two hours. At 46, she had to take medical leave from her
job at a bank in the city of Aberdeen on the Pacific coast of Washington
state. Finally, after a year of medical tests that found nothing, she was
diagnosed as having chronic fatigue syndrome (CFS). ‘That was about all
there was left,’ she says dryly. ‘It’s a disease diagnosed by exclusion.’

Now, after four years, she says she is ‘infinitesimally’ better, as
measured by the fact that she can do simple exercises. Her prognosis? ‘I’m
not going to die, but with chronic fatigue syndrome you don’t ever get your
life back. It will never be the same.’ The cause? Lucy says that from all
she has learnt about her condition, she suspects that a double bout of a
bad throat infection triggered the condition, but her doctors tell her the
real cause is a ‘unique retrovirus’.

Elusive causes

Maybe. Maybe not. The fact is that while numerous theories exist, some
with supporting evidence, the cause of chronic fatigue syndrome, more commonly
referred to in Britain as myalgic encephalomyelitis (ME) or postviral fatigue
syndrome, remains elusive.

Yet many doctors still don’t refer to it as a disease; no diagnostic
test is available and symptoms are treated by trial and error. That is
why the catch-all term ‘syndrome’ is often used to describe the various
symptoms. These include fevers, tenderness in the lymph nodes, muscle fatigue
and pain, depression and exhaustion.

But some scientists believe they are homing in on the causes and effects
of the illness. ‘Researchers have a more sophisticated appreciation of
the questions to be answered,’ says Keiji Fukuda, a medical epidemiologist
at the Centers for Disease Control and Prevention, the US government agency
that deals with public health problems.

Some of these questions, and maybe some answers too, will be aired next
week when more than 150 clinicians and medical researchers meet in Dublin
at one of the few conferences on CFS to be held outside the US. This meeting,
the International Meeting on Chronic Fatigue Syndrome, has attracted researchers
from a large number of countries who are bringing promising new leads to
the cause of the illness. They will discuss the results of several surveys
that indicate CFS may be more widespread than once thought.

During the past decade, much progress has been made in characterising
CFS. No longer is it universally dismissed by doctors as a behaviour-based
psychological problem. Over the past five years, lobbying by patient groups
in the US has helped to increase funding for research into the illness.
As a result there are now a plethora of laboratories working on different
aspects of the illness. Combined with research in other countries, such
as single photon emission tomography studies at University College London
that showed lower than normal blood flow in the brains of ME sufferers,
this surge of interest has conferred some scientific respectability on the
syndrome.

The 1980s label of ‘yuppie flu’ was indicative of the way the disease
was then seen: a disorder of the self-absorbed professional middle class,
that was primarily psychological in origin. Now the pejorative name and
the ideas that went with it have gone, even if some doctors still believe
chronic fatigue syndrome to be rooted in the mind, because many patients
show signs of depression. But an increasing number of researchers think
biological and psychological factors are intertwined, and that an organic
factor may soon be teased out. In fact, before the name chronic fatigue
syndrome was adopted in the US in 1988, the illness had a variety of names
and descriptions including chronic Epstein-Barr virus, postpolio virus and
postviral fatigue syndrome. Now, to highlight what they believe to be the
disorder’s organic roots, patient groups in the US call it chronic fatigue
and immune dysfunction syndrome (CFIDS).

Meanwhile, Ellen Goudsmit, director of the International Federation
of the Myalgic Encephalomyelitis Association based in Middlesex, prefers
to use ME to refer to CFS-like disorders believed to have a biological basis
and CFS to describe a broader range of illnesses where one of the symptoms
is fatigue.

Many theories as to the primary cause of the biological disease still
focus on viruses as the culprits. But some of those that have been targeted
and investigated no longer look like likely candidates. This has not deterred
other researchers looking for an organic explanation for CFS. Some of the
most compelling evidence for a biological basis for the disease comes from
studies of symptoms of CFS. If any theory prevails in the US, it is that
symptoms of the illness reflect ‘an unusual and inappropriate immune response’,
says Paul Levine, a researcher at the National Cancer Institute in Bethesda
who is also president of the American Association for Chronic Fatigue Syndrome.

This model has been advanced through findings that patients have disturbances
in cellular immune mechanisms, which can be either excessive or deficient.
Some researchers, for example, have seen patients with a rise in the number
of cytokines produced by their immune system’s helper T cells, the white
blood cells that initiate many immune system responses. Cytokines are proteins
that encourage the immune response by prompting immune cell growth and activation,
directing cellular traffic and enabling macrophages to devour bacteria and
other foreign material. But the energy needed to produce an endless supply
of cytokines, plus the stress of constant immune system activity, is enough
to make a person quite literally sick and tired. Proponents of this model
suggest this immune response could be due to the reactivation of childhood
viruses after an initial immune response to a new infection. Other researchers
have reported seeing patients with defects in large lymphocytes known as
natural killer cells or low numbers and imperfect function of other T cells.
But evidence is inconclusive, says Levine, and none of these conditions
is unique to CFS.

Sick cells

The heightened immune response represented by high levels of cytokines
has also led some people to think that CFS is an autoimmune disease. It
can, indeed, look like an autoimmune disease, Levine comments. In autoimmune
diseases such as certain forms of arthritis, the immune system goes into
disarray without there being any external trigger, such as a virus.

Fukuda warns that researchers’ findings may reflect their own research
biases, given that the definition of CFS is vague. According to the CDC’s
definition, patients have CFS if they suffer from severe chronic fatigue
plus eight of the following signs and symptoms: chills or low-grade fever,
sore throat, tender lymph nodes, muscle pain, muscle weakness, extreme fatigue,
headaches, joint pain (without swelling), neurological problems, sleep disorders,
acute inflammation of the pharynx, and sudden onset of symptoms.

‘The current difficulty in interpreting any of these studies is that
not everyone is using the same definition,’ says Fukuda. Investigators may
not stick strictly to the CDC definition, and may not make this clear in
their publications, he says. For that reason and because the science of
CFS has advanced since the original definition was published in 1988, the
CDC is now working on clearer guidelines, to be published this year.

Peter Behan, professor of clinical neurology at the University of Glasgow
and organiser of the Dublin conference, freely admits that he thinks the
CDC’s definition of the disease is inadequate, and that he follows his own,
which includes even more clinical parameters, such as persistent diarrhoea
and abrupt mood changes that can resemble epilepsy.

Behan says that several papers to be presented at the conference offer
new evidence that the illness is due to factors that upset a cell’s production
of energy. The cell’s energy currency is adenosine triphosphate (ATP), and
its production is mediated by a host of enzymes. Behan suggests that some
of these enzymes may malfunction if a person is exposed to toxins such
as heavy metals, some organophosphates such as those used as insecticides,
and even viral infection. His view is that the strongest data to be presented
at the conference points to CFS as a metabolic disease.

In his own work, Behan has shown that levels of the enzyme calcium ATPase,
which allows calcium ions to move into the cell to help produce ATP, are
abnormally raised in people with CFS. Submitting muscle tissue to nuclear
magnetic resonance, he found that CFS patients who exercise have a low rate
of oxygen consumption. At the same time, the lactic acid they produce in
their muscles is significantly increased, which also suggests that oxygen
is scarce. Glucose in their muscles is rapidly broken down and, under an
electron microscope, muscle cell mitochondria can be seen to be swollen
and skewed, says Behan. The internal membrane structure of the mitochondria
also breaks down. ‘All this evidence tells us that the mitochondria are
sick in the CFS patients we studied,’ Behan explains.

Mind-body problem?

Behan says that work to be presented by Australian researchers fits
in nicely with his theories. John Pearn, a paediatrics professor at the
University of Queensland in Brisbane, has found that a number of patients
with CFS suffered initially with a type of poisoning called ciguatera, caused
by eating fish that carry the toxic protozoan Gambierdiscus toxicus. Patients
who ate the infected fish first suffered severe gastrointestinal problems,
followed in some cases by the symptoms of CFS. G. toxicus damages enzymes
by interfering with the transport of calcium and sodium into cells, and
the researchers believe it is this which produces abnormal cellular respiration.

Behan believes that more support for his theory is provided by work
at the University of Leeds, which suggests that muscle cells in patients
with CFS contain inadequate supplies of the ions they need for the production
of ATP. They also found low levels of phosphate, which is involved in the
production of ATP. Behan hopes that this might show the way to a diagnostic
test involving the measurement of the level of phosphate in muscle cells.
It could even, eventually, lead to a possible treatment, such as some form
of phosphate replacement.

But Fukuda, among others, is not ready to accept Behan’s theories. He
points out that much work still needs to be done to explain all the ramifications
of CFS, including the psychological distress. His unwillingness to exclude
psychological factors mirrors the primary position of the National Institute
of Allergy and Infectious Diseases, which has recently said that CFS may
be the prime example of a ‘mind-body illness’. Mark Demitrack, assistant
professor of psychiatry at the University of Michigan Medical Center, takes
a similar view in an article in the February issue of Annals of Medicine,
in which he suggests that the causes of CFS may be as complex as the factors
that lead to conditions such as hypertension.

Demitrack bases his argument on his study of hormone disturbances in
the brain’s hypothalamic pituitary adrenal (HPA) axis, which controls the
hormone stress system in the body. He says that CFS patients frequently
report the onset of their illness following a significant period of stress,
such as emotional trauma, overwork or sleep disruption, and that the course
of the syndrome waxes and wanes with subsequent periods of physical or emotional
stress. Demitrack and others have found that levels of hormones such as
cortisol, which are stimulated by stress, are slightly lower in CFS patients,
and he believes that HPA functioning in general is depressed in this group,
resulting in CFS symptoms.

One clinician, Peter Manu, doesn’t need any convincing that CFS has
a psychological component. Manu, director of medical services at Hillside
Hospital in New York, finds that the patients with CFS whom he treats get
better when he convinces them to stop working so hard. ‘A lot of patients,
instead of working 16 hours a day, all of a sudden work 8 hours a day and
feel better,’ he says.

Fukuda sees Manu’s views as ‘simply a theory at this time’, although
he accepts that they may be valid ‘for a small subset of patients’. Behan,
however, dismisses any idea that CFS is controlled by the mind. He says
that much research has shown that mental stress in these patients is quite
different from that seen in classic depression. ‘They have excessive sleep,
no guilt, no delusions, no decrease in interest in projects or sex,’ he
says.

Behan sees dangers in following the psychological approach. ‘It’s absolutely
retrogressive to suggest CFS is in the heads of patients,’ says Behan.
‘I have seen patients commit suicide, or have been otherwise destroyed,
because some professor has diagnosed them as having a psychiatric illness.