Chronic Fatigue Syndrome is no longer seen as being "all in the mind". Its true nature is still unclear, but researchers are slowly closing in.

A MYSTERIOUS epidemic spread through the Los Angeles County Hospital, in California, in 1934. Nurses and doctors succumbed to a strange mix of fatigue, muscle pain and emotional distress. The first suspect was polio-the symptoms were similar, and fear of the disease was rampant at the time. Yet tests for polio revealed nothing and, bizarrely, the hospital's patients remained unaffected. A similar pattern of events occurred in 1955, at the Royal Free Hospital in London. Again, patients were untouched. And in both cases, most of those who succumbed were women.

Many people would now be familiar with these symptoms. They have gone under a variety of names in the 19th century, they were referred to as neurasthenia. In the wake of the 1955 outbreak the term myalgic encephalomyelitis (or ME) was coined. More recently the complaint has been derisively referred to as "yuppie flu". And now Chronic Fatigue Syndrome (CFS) has become the preferred label. The changes of name have not been accompanied by much change in understanding, however. Nobody yet knows what causes CFS. But at a recent meeting in London, held under the auspices of the Novartis Foundation and the Linbury Trust, a group of experts got together to exchange their latest theories.

The first problem with CFS is agreeing who has it. Since fatigue cannot be measured objectively, deciding who crosses the hazy line between normal lack of energy and abnormal tiredness is tricky. The boom-and-bust appearance of CFS and its antecedents (neurasthenia was fashionable among the Victorian upper classes, and often required prolonged rest cures at spas), has led some doctors to dismiss the whole thing as mass hysteria.

With one recent survey in Britain suggesting that 30% of women and 19% of men always feel tired, there is plenty of scope for over-diagnosis of CFS. But the syndrome is more than fatigue, whether physical or mental its other symptoms include weakness, muscular pain, disturbed moods and problems with sleep. These can be measured and they can then be researched.

Know thyself

The first of these problems yields a mystery. CFS patients insist that their muscles do not respond to their desires. But despite intensive investigation, researchers have found no particular muscular weakness or abnormality that could account for the patients' complaints. It is true that the syndrome takes its toll on a patient's muscles. Arid as movement consumes more energy than patients can muster, they opt for inactivity. That plunges them into a downward spiral of weakness, since unused muscle tends to feel powerless. But there is no sign of a problem in the muscle itself, so the disruption must lie in the nervous system that drives it.

Daniel Wolpert, a cognitive neuroscientist at the Institute of Neurology in London, who spoke at the meeting, offered one explanation of why people suffering from CFS consider themselves to be more tired than the tests suggest they should be. His theory is based on the widely held idea that the brain harbours a model of the body that it uses to predict the consequences of movement. If you wave your arm, the muscles transmit signals to a part of the brain called the cerebellum, which "examines" the model, makes predictions and then alerts the rest of the brain about what sensations it should look out for. This explains, for example, why people cannot tickle themselves: their brains know what to expect, and can thus cancel out the sensation.

Dr Wolpert's suggestion is that people with CFS may have lost this self-predicting loop and so cannot cancel out the sensations returning from their muscles, even when those muscles are moving under willpower. Every exertion thus appears to be loaded with unwarranted effort. The natural reaction is, therefore, to avoid that effort.

Tony David, a clinical psychiatrist at the Institute of Psychiatry in London, is another researcher who thinks that problems of self-awareness are central to the syndrome. In his view, CFS has a lot in common with anorexia nervosa. Anorexic people often see themselves as fat even though others find them almost painfully thin. Anorexics can estimate their height quite accurately when they stand in front of a mirror. But they tend to overestimate the width of their hips, waist, legs and faces by around 30%. Dr David reckons that a similar bias in self-perception is present in CFS patients, who perform much better in tests of strength and intelligence than they expect.

The notion that CFS is a disorder of perception is also supported by the fact that around two-thirds of patients with the syndrome can be helped by cognitive behaviour therapy. Under this approach, they are given small tasks that gradually get harder as the treatment progresses. By slowly adapting to the increasing activity, they no longer perceive their effort as excessive. With this opportunity to gain control gradually, they learn to cope with the illness.

Another defining symptom of CFS is poor sleep. Patients still need sleep, but they find it hard to nod off. As a result, they end up spending longer in bed, probably to compensate for their fragmented sleep patterns. Jim Waterhouse and his colleagues at Liverpool John Moores University, led by Gareth Williams, are studying the body's clock-the circadian rhythm. Dr Waterhouse is convinced that this clock is involved in CFS.

Although falling asleep requires no conscious effort, it is still a major physiological feat that requires carefully choreographed body changes. For drowsiness to set in, the body's temperature must drop. Usually it does so rapidly, within one or two hours. At the same time, the pineal gland in the brain pumps out a hormone called melatonin. This combination is the signal to go to sleep. In people who nod off easily, the two events are tightly synchronised. In CFS patients, however, they are mismatched. Worse, their melatonin production is not as efficient as it should be. And when Greg Tooley, another member of the group, recorded the temperature cycles of such patients, he found that their evening drop in temperature happened an hour or two later than normal. An hour's lag may not seem that much, as most people can function reasonably well if deprived of one or two hours' sleep for a night. But if the discrepancy persists, it might bring on the full-blown symptoms of severe sleep deprivation. Fatigue is one of them.

The researchers at John Moores are trying to find out whether melatonin pills can help CFS patients fall asleep. In an initial trial, they arranged for 31 subjects to take melatonin every evening at 5 o'clock, for three months. For comparison, each patient also took a placebo tablet for three months, without being told which was which. The preliminary results are promising. The participants slept better, felt less haggard, and even reported themselves to be more cheerful while taking melatonin. Their temperature also declined earlier in the evening.

These are promising approaches. But prevention is better than cure-and that will only be possible when the cause of CFS is identified. One common misconception can be discounted, CFS is not a politically correct alternative name for clinical depression. Depressed patients are characterised by a lack of motivation; people with CFS want to go about their daily business, but are frustrated because they cannot summon the strength to do so. And whereas depression can often be treated with a class of drugs called selective serotonin-reuptake inhibitors-the best known of which is Prozac - these do not work in people with chronic fatigue.

One persistent idea is that the disease is triggered by an infection. Peter White, a researcher at St Bartholomew's Hospital in London, reckons two-thirds of CFS cases may start this way. Dr White studied 250 people with either glandular fever or (for comparison purposes) a common throat infection. Six months after the infection, over 9% of the patients who had had glandular fever were chronically fatigued, against none in the control group.

The list of suspect infections is, however, a long one. It includes Epstein-Barr virus (the main cause of glandular fever), hepatitis types A, B, and C, viral meningitis, toxoplasmosis, cytomegalovirus and a rare illness called Q fever. (With hepatitis B and C, the continuing infection may be the cause of fatigue rather than CFS itself.) What such a disparate collection of diseases has in common is unclear, though they all excite the immune system into secreting substances called cytokines which are known to cause fever, disturbed sleep, aches and fatigue.

The mystery of CFS, then, is by no means solved. But at least it seems that progress is being made in diagnosis - and the first steps are being taken towards a cure.