What causes mononucleosis, triggered by the Epstein-Barr virus, to lead to chronic fatigue syndrome (ME/CFS) in some people? (Photo: Colourbox)

Few physical differences found between healthy individuals and those afflicted by chronic fatigue syndrome

Norwegian researchers studied adolescents who developed chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF) after having mononucleosis.

Chronic fatigue syndrome (ME/CFS) affects thousands of people in Norway.

Little is understood about the cause of the disease, but research has shown that it can be triggered by infections. Many people develop ME/CFS following a bout of mononucleosis – sometimes called mono or “the kissing disease” – which is a viral infection caused by the Epstein-Barr virus.

But not everyone who gets mono ends up with chronic fatigue syndrome. What separates those who get ME/CFS from those who don’t? Understanding these differences could give us hints about which mechanisms are behind ME/CFS.

The results of a Norwegian study that explored this very question have now been published.

Different interpretations

The results show some small differences in the immune system between people who regain their health and those who develop ME/CFS or other chronic fatigue after mono, but not enough to explain the dramatic disparity in symptoms.

Professor Vegard Bruun Bratholm Wyller led the study and believes the results support the hypothesis that ME/CFS is due to a hypersensitivity in the brain. This leads to signals from the outside world being over-interpreted because the nervous system is on continuous high alert.

Professor and paediatrician Kristian Sommerfelt, on the other hand, believes that the results only show that the participants with a lot of symptoms after their bout with mono more often develop chronic fatigue, and in some cases chronic fatigue syndrome.

He notes that brain hypersensitivity was not investigated in this study.

Almost half developed CF or ME/CFS

Wyller and his colleagues recruited a group of about 200 adolescents between the ages of 12 and 20, who had just been diagnosed with mononucleosis. In addition, they included a healthy control group without the illness. Researchers followed up on both groups six months later.

The participants completed a questionnaire on their symptoms, and the researchers ran several different tests that could reveal something about disparities, for example in the immune system or the hormone balance.

After six months, 91 of the participants had developed chronic fatigue. Of these, 26 met the so-called Fukuda criteria for ME/CFS. Slightly fewer – 19 participants – had ME/CFS according to the strict Canadian consensus criteria.

Small physical differences

The participants with chronic fatigue had a number of bodily symptoms that were stronger than those with no CF. These included symptoms of infection, palpitations, extreme fatigue after little effort and severe discomfort from being in an upright position.

But blood tests showed only very small differences between all the groups – the adolescents who had mono and those who didn’t, and participants with mono who were healthy again and participants who had developed CF or ME/CFS.

These small differences in the blood could not explain the large disparity of symptoms.

Nor did measurements of the mono virus in the body indicate that the participants with chronic fatigue had stronger infections.

Researcher and paediatrician Kristian Sommerfelt has been working with children with ME/CFS for decades. He believes the new study is solid.

“This study reflects thorough work,” he says.

“It’s important to pursue a genuine search for causes, and this study has contributed to that, but without finding any cause.”

Missing clear signs

The study joins a series of research studies that have struggled to find clear and unambiguous differences between healthy people and people with ME/CFS.

A number of them have shown small distinctions between groups of healthy individuals and ME/CFS patients, such as in the immune system and the metabolism. But researchers have not succeeded in finding samples called biomarkers that clearly distinguish the individual ME/CFS patients from healthy individuals.

In many cases, it’s also not possible to say whether the differences between the groups are the cause of the disease or the result of it.

Recently, US researchers presented a possible biomarker, but the finding needs to be confirmed before anything is known for sure.

This lack of clear answers opens the door to very different interpretations of the research.

Thinks the brain rules

"Overall, this suggests that ME/CFS and CF are about how the brain perceives the body, not how the body actually is," Wyller says.

He compares this with chronic pain. “You can have a lot of pain without finding anything wrong in your body. It's about how the nervous system responds,” he says.

The research on pain has shown that the nervous system can change, for example after a physical injury, so that it begins to perceive signals differently. It simply rebuilds so that certain signals – like touch or heat and cold – are suddenly perceived as pain instead.

A lot suggests that the pain level you feel may depend at least as much on how the brain responds to it as on what kind of stress you are physically exposed to.

Other studies have shown that normal fatigue after exercise is also controlled more from the brain than from the muscles. When top athletes give their all and collapse on the goal line, the muscles in fact still have strength left, but the brain says stop.

Wyller believes similar mechanisms are at work with ME/CFS, where the brain is somehow suspended in perpetual high alert, and normal signals from the outside world get over-interpreted.

He believes the lack of clear differences in the immune system give credence to this hypothesis.

"I am quite convinced that functional changes in the brain play a key role, which means that psychological processes are important," he says.

Skeptical of suspended brain idea

Sommerfelt sees things in a completely different way.

He believes there is no good research to support the view that ME/CFS is caused by the brain putting the body in constant state of high alert, even though the hypothesis cannot be ruled out.

A previous thorough study done by Wyller's research group goes against the idea, Sommerfelt says. In that study, ME/CFS patients were given the drug clonidine, which suppresses stress reactions. However, it turned out that the drug did not cause fewer fatigue symptoms.

Sommerfelt believes the findings from the new study are compatible with many hypotheses about cause, including Wyller's hypothesis.

He nevertheless thinks that it is much more likely that mono impacts the immune system, which in turn alters the regulatory mechanisms that include the brain. This can happen in very complex ways that may not have been captured by the measurement methods in this study, says Sommerfelt.

Changing the brain through conversation therapy

The disagreements between the two professionals are reflected in the opinions they have about how the disease can be treated.

Wyller also believes that purely bodily mechanisms play an important role and that various mechanisms can lead to ME/CFS.

“This is no different than with other diseases, like heart disease. For some people, genes are the main cause, while for others it’s their lifestyle,” he says.

“But I'm sceptical of a purely biomedical approach to chronic fatigue syndrome. Changing the brain may work as well through conversation as with drugs,” he adds.

Disagreement on cognitive therapy

Wyller believes several studies show that cognitive behavioural therapy is effective.

The organization Recovery Norway has gathered about 50 testimonials from people who overcame ME/CFS after using psychological methods.

"The brain is plastic, and this should be good news for patients," says Wyller.

But not all ME/CFS patients have had a positive experience with this type of treatment.

Norway’s ME Association's user survey from 2013 found that approximately one third of the 1100 survey participants stated that they had tried cognitive therapy. The vast majority experienced no positive effect. Some stated that their condition worsened.

Coping strategies important

Paediatrician Sommerfelt does not agree with Wyller that cognitive therapy works well for strictly defined ME/CFS cases.

“There isn’t any support for cognitive therapy being an effective treatment. Some individuals benefit from cognitive therapy or other coping strategies, but not many,” he says.

However, Sommerfelt agrees that a purely biomedical perspective is a poor approach in virtually all diseases, especially chronic and taxing illnesses like ME/CFS.

“Coping strategies are very important,” he says.

The paediatrician believes it is likely that some patients with chronic fatigue that fall outside the strict criteria for ME/CFS may have symptoms due to causes that can be treated well with cognitive therapy.

“But it’s important not to mix apples and oranges here,” he says.

“A long-standing and solid tradition in medicine holds that diseases and conditions that you do not understand should first be defined strictly by research, because it reduces the chance of actually examining several different diseases or causal mechanisms at once,” says Sommerfelt.

International disagreement

Why do professionals in the field interpret the existing research material so differently?

“I think this shows that research always happens against a backdrop of one's own perceptions,” says Wyller.

And the phenomenon applies to researchers in many countries. The disagreement among professionals is reflected in strikingly different official information on treatment.

NHS, the UK health authority, recommends cognitive behavioural therapy and graded exercise therapy – a customized training programme aimed at increasing activity levels over time.

However, the US Center for Disease Control website warns against too much activity. Instead, they advise patients to avoid the crashes brought on by too much physical and mental effort, and suggest finding a level where they remain stable.

The CDC barely mentions cognitive therapy. It only appears as a tool for treating anxiety and depression if a patient has these symptoms in addition to ME/CFS.

Only when our knowledge base about the disease grows and becomes less ambiguous, are viewpoints likely to converge on what causes ME/CFS and how the disease should be treated.


Read the Norwegian version of this article at forskning.no

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