In the September 1990 issue of 'Emerge', I wrote an article titled 'Where do things stand with CFS at this time...?' With the following article, I wish to summarise what has happened since then.

Definition of CFS

The various diagnostic criteria have changed little since their initial definition, however there is still no one internationally accepted diagnostic criterion for clinical or research use as many countries have their own. Variations in the listed symptoms exist between each country's criterion. There is also still no widely accepted diagnostic test available for CFS, although some current research shows promise in this area. The peer reviewed medical journals are the only way that these potential diagnostic tests can gain wide acceptance by the medical profession. This process firstly involves publication in the medical journals. The studies must then stand up to scrutiny and must be able to be reproduced by other researchers.

The term 'Chronic Fatigue Syndrome' is the most widely used term here in Australia and as such continues to cause difficulties for those involved with the illness, due to the name's inability to accurately describe the reality of this condition. The term 'Myalgic Encephalomyelitis', which is the medical term for the illness, is also inaccurate. There is a push to come up with a better name for the illness from a group in the USA, however this task is difficult until CFS is better understood and more easily definable.

Awareness

Since I wrote the first version of this article in 1990, I think that public and professional awareness in Australia has been the main area of progress. Many more people these days have heard of CFS and comments like "I know someone who has CFS" are not uncommon. But some people still don't have an accurate understanding of CFS symptoms and how serious they can be. The medical profession have experienced an increase in awareness due to the growing number of published articles in doctors' magazines and medical journals, and direct education from patients.

The government's main medical research funding body, the NHMRC, has still not funded a single study into the organic basis of CFS. However political lobbying has resulted in the setting up of a CFS working group with the aim of producing guidelines on the diagnosis, treatment and management of Chronic Fatigue Syndrome. These guidelines will be published in the Medical Journal of Australia and will be made available to all general practitioners in Australia. They will be significant in that they should act as a reference and standardise the processes involved in handling CFS cases.

International CFS Awareness Day, held on May 12th each year, has been an excellent vehicle for making further gains into community awareness of CFS, with wide media coverage each year.

Despite the improvements in awareness, there is still some ignorance, misinformation and lack of compassion present throughout the community. Even though the situation has improved compared with several years ago, the excellent efforts undertaken by members of the CFS community to increase awareness and education must continue for some time yet.

Research

The search for the illusive cause continues. One of the difficulties experienced by many studies when an abnormality is found, is that it is difficult to know if this abnormality is the cause of the illness, a secondary condition which causes some or no symptoms, or is totally unrelated. I will now discuss the main areas of research.

Immune System
The immune system has been much studied in CFS and was once thought to be central to the illness. A range of abnormalities have been found, including changes in cell numbers and behaviour, and immune system chemical changes, but often only in a proportion of patients. Sometimes these changes are only transient. Lack of consistent results have led most researchers to conclude that these abnormalities are probably only secondary to the illness. Immunological treatments such as alpha-interferon, Ampligen and SRL172 are being studied and may be beneficial to a subgroup of patients.

Specific immune system abnormalities include evidence of immune activation, changes in natural killer cell activity and disordered cell mediated immunity. Cytokines are powerful immune system chemicals and can result in many 'flu like symptoms similar to CFS. Several studies have tried to detect abnormal cytokine levels without producing consistent results. However, most of these studies have measured cytokines on a general scale such as in the blood. It has recently been established that cytokines can be produced at a local level within parts of the brain. This phenomenon can produce symptoms but is difficult to measure. Research in this area is continuing.

Muscle Function
Most studies have reported normal muscle functioning, although some abnormalities have been detected, including a possible muscle membrane abnormality, defect in oxidative metabolism and cellular protein synthesis, and early acidosis.

Blood
Research is still being done on red blood cell shape, although nothing significant has been published to date. Some very convincing research was published which showed reduced blood flow to parts of the brain (hypothalamus, brain stem and frontal or parietal lobes) using SPECT scans. This finding has not been replicated in any other medical or psychiatric conditions.

Pesticides
These published studies remain controversial, one completed by the University of Newcastle and the other by Dr Behan from the UK. They found higher levels of pesticides in CFS patients compared to healthy controls. The meaning of these results remains unclear. It could be that the ability of CFS patients to remove toxins from their body is reduced, rather than high levels causing the illness in the first place. However, it is also possible that an initial exposure could trigger CFS in susceptible individuals.

Hormones
Hypothalamic function studies have demonstrated abnormalities in serotonin and acetylcholine which are chemical transmitters. Hormone levels have been studied with abnormal levels detected in arginine-vasopressin, growth hormone, mild low cortisol levels and upregulation of 5-hydroxytryptamine (involved in temperature regulation).

Psychiatry
This is still a controversial area as the relationship between psychiatric illness and CFS is complex and not fully understood. However several studies have shown a distinct difference between measurable parameters in CFS and some psychiatric illnesses like depression. Other studies have shown that CFS sufferers were no more likely to have a psychiatric illness prior to the onset of CFS than the normal population, and that the incidence of psychiatric symptoms during the course of their illness is very similar to other medical conditions which have a similarly disruptive affect on a person's life.

Prozac (or fluoxetine, a commonly used antidepressant) was shown to have no beneficial effect on any characteristic of CFS, which added to the evidence that CFS was not simply depression. However, another commonly used antidepressant, moclobemide, was shown to be of benefit to a proportion of CFS patients whether they were depressed or not. It is believed that its effects on certain neurotransmitters and its benefits in those CFS patient's with impaired cell-mediated immunity seems to be important.

Excretory metabolites
Researchers at the University of Newcastle in Australia have demonstrated abnormal levels of metabolites excreted in the urine. The link to the metabolic processes involved is still little understood, but may offer hope of some improvement in symptoms if these levels are corrected. This research is ongoing and several further papers are due for release soon.

Infective agents
The search for a single viral cause of CFS has so far failed. Some evidence of retroviral involvement has not been replicated. One research group is still studying a possible 'stealth-virus', however sample numbers used were very small and results are still controversial. Most researchers now believe that CFS is not likely to be caused by a single virus. More importantly, viral infections, along with many other factors seem to act as trigger agents which begin the medical process termed CFS. Viruses may then help to perpetuate, or worsen the illness. Reactivation of dormant viruses, such as EBV and persisting enteroviral and HHV-6 infections seem to be more common in CFS, possibly due to a disordered immune system.

Accumulation of certain bacterial toxins may also add to the symptoms of CFS, as found by the University of Newcastle. One in particular, named CFSUM1, seems to be of particular importance and may cause direct symptoms if present in high enough levels.

Hypothalamic-Pituitary Axis (HPA)
These two areas of the brain play important roles in controlling many vital functions in the body. Both release hormones and measurable abnormalities in these have been found. Many researchers now consider the HPA to play an important, possibly central role, in CFS. One theory states that a short lived infection dysregulates the HPA which persists, causing secondary brain dysfunction which then goes on to affect other organs in the body.

Other research
Studies in other areas have found some cardiac dysfunction and sleep disturbances. A small study reported by Suhadolnik indicated a significant fault in the 2-5A Synthetase/RNase L antiviral pathway. He believes that this enzyme is also important in controlling metabolism overall. This abnormality was not found in any of the healthy people studied and has been replicated by two other research groups. This research holds promise for a test and possibly a treatment if it is shown to be central to the condition. Larger studies are underway, and must be published before any conclusions can be made.

No evidence has been found that hyperventilation forms part of CFS. The John Hopkins Institute have reported that neurally mediated hypotension (a blood pressure abnormality) has been found in a subgroup of patients. Once again, it seems that this abnormality is only secondary to CFS and not the cause for most patients. Gulf War Syndrome has also experienced an uphill battle for recognition. This illness shares many symptoms in common with CFS and research into this condition may also benefit CFS.

Treatment
No treatment has been shown to benefit all CFS patients. Many drugs and supplements have never been properly medically trialed in CFS, so any claims made cannot be substantiated. Intravenous immunoglobulin therapy has been trailed by a few research groups. It was found that limited, usually short-lived benefits were outweighed by the cost of therapy and limited availability.

Medical trials have shown the following treatments to be of no benefit in CFS including fluoxetine (Prozac), transfer factor, cognitive behaviour therapy, vitamin B12 supplementation and the antiviral drug acyclovir. On the other hand, subgroups of patients have gained benefits from moclobemide, high dose evening primrose oil and magnesium sulphate injection.

Conclusion
Many abnormalities have been listed above which add to the mounting evidence that CFS is an organic illness. Piecing it all together is a complex and overwhelming task, however the main conclusion which can be made so far is that whatever the central cause of CFS is, it has a significant and disruptive effect on a range of bodily functions which are being identified as more research is being done.

As time goes on, researchers will home in, and eventually find the one or several underlying causes of the illness, which will lead to a much needed diagnostic test and treatment.

Bernhard Liedtke

Reprinted from Emerge, September 1997.