The strange case of chronic fatigue syndrome




«Undoubtedly, the perverse use of CFS, to impose a psychiatric definition for ME/CFS by associating it with fatigue syndromes, has delayed research, the discovery of effective treatment(s), and care and support for those with this illness.«
Hooper 2007
Having a background and an interest in metabolism I am intrigued by reports about chronic fatigue syndrome. I have been looking around a bit, mostly pubmed searches, and have learned some interesting things. I´ll put it her if anyone else might be interested. I am thinking that this bizarre condition that renders some bed bound in pain and unable to move or even communicate by normal means, must be related to a metabolic defect in some way. And if so, what’s food got to do with it?

Definition
Chronic fatigue syndrome is a chronic multiple-symptom, multiple-organ illness. Its proper name is Myalgic Encephalomyelitis (ME). The name implies diffuse muscle pains related to an inflammation of the brain and/or spinal cord.
The main symptoms of the ME diagnosis is muscular pain and chronic fatigue. Other common symptoms include headaches, gastrointestinal disturbance, joint pains and paresthesia, post-exertional malaise; cognitive difficulties with impaired memory and concentration; unrefreshing sleep patterns (lack of deep sleep) and mood changes.
Myalgic Encephalomyelitis is a specific clinical condition that characterizes unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months (3 for children), in the absence of a medical diagnosis that would otherwise explain the clinical presentation.
Although many claim that there are no valid laboratory tests to be done several scientists beg to differ. Professor Malcolm Hooper of University of Sunderland is one who strongly disagrees and refers to the Canadian report, “Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols”. It lists a whole range of tests to be done, ranging from muscle strength, memory test, standing and lying blood pressure andhormone assessments to serum trace minerals and inflammatory cytokines.
The diagnosis of ME is not clear cut and many patients with fatigue as a major feature of their illness like cancer, chronic obstructive pulmonary disease and depression, are being diagnosed with ME. After the Gulf War the syndrome known as Gulf War syndrome has been labeled the myalgic encephalomyelitis of the military. It is a frequent diagnosis in the medical records of veterans of the first Gulf War, where it is commonly named as CFS.
Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years. These findings implicate that whatever causes ME might also cause cardio-vascular disorder, although it might simply be a correlation without causation.
It is clear from the literature that ME is not one specific disease or illness, but rather a group of symptoms regularly coexisting much like how the metabolic syndrome is just a group of risk factors for diabetes and cardiovascular disease.  
According to Fernández et al (2009) the estimated worldwide prevalence of ME is somewhere between 0.5-2.5%.  It is also more common in women than in men.

But what is ME?
Although relating to a great range of symptoms, ME patients do seem to have one common denominator. Various groups of scientists have studied the gene expression in blood of patients with ME, and from those studies it is clear that the major functional theme is that of immunity and defense – defense referring to immune response to external microorganisms.
Epidemiological studies have shown that many patients with MS have a history of illness consistent with viral infection that precedes the development of fatigue symptoms. In fact most patients diagnosed with ME seem to recently have had a viral infection and ME has been shown to follow acute infection with various infectious agents.
In Norway during the fall of 2004 about 5000 people in the city of Bergen was infected by the parasite Giardia. Sewer had leaked into to city’s water reservoir. The Hospital in Bergen reported that more than 100 people experienced acute fatigue in the period after the infection of who more that 20 people was diagnosed with ME. The number far exceeds the number normally being diagnosed.
Although patients with ME have been shown to have evidence of immune activation, despite considerable research, the causative and perpetuating disease mechanisms still remain unknown.

Mechanisms
Studies have uncovered several genes that are expressed in those with ME that are not expressed in healthy controls. These genes are involved in several processes, including immunity and defense, the mitochondria, and transcriptional and translational regulation.
ME is also highly correlated with fibromyalgia, the line between fibromyalgia and ME is far from clear and many patients have had both diagnoses. By criterial definition, pain is the major feature of fibromyalgia whereas post exertional malaise and fatigue are the major symptoms of ME. It is likely that they may have a common cause. Fibromyalgia is also just a collection of symptoms similar to those of ME. In the end it seems it is just two sides of the same coin.
As stated, infections are often seen to precede ME, as was the case in Bergen. There is also the case of a Los Angeles County Hospital epidemic of 1934 and the Royal Free Hospital epidemic of 1955, which are consistent with viral infections.
A severe flu-like illness occurs in most cases of ME, suggesting that an infection triggers and possibly perpetuates the syndrome. Common viral infections and unusual causes of ME can be diagnosed on the basis of the details of the initial flu-like illness.
Also, immune system changes in myalgic encephalomyelitis tend to point to reduced natural killer cell activity, reduced Th1 cell activity (sub group of white blood cells), increased Th2 cell activity (also a sub group) and increased cytotoxic T cell activity.
Recent evidence comes from a study by Kaushik et al. (2005). They studied gene expression in peripheral blood mononuclear cells in 25 patients with chronic fatigue syndrome compared with 25 normal blood donors matched for age, sex and geographical location. One of their findings was up regulation of a mitochondrial translation initiation factor, a result that is consistent with a persistent virus infection.
It has also been suggested that ME is related to the handling of long-chain polyunsaturated fatty acids. A viral infection could adversely affect the biosynthesis of long-chain polyunsaturated fatty acids and therefore the membrane structure, functioning and production of eicosanoids. Viral infections can impair the ability to biosynthesize long-chain polyunsaturated fatty acids from their short-chain precursors.
Immune response in ME patients is often impaired, as seen by elevated levels of interferon alpha, transforming growth factor beta, interleukin-4, interleukin-6, interleukin-1 alpha, and tumor necrosis factor alpha (TNF-α). The observed high levels of pro-inflammatory cytokines may explain some of the manifestations of ME such as fatigue and the flu-like symptoms.
Fulle et al (2000) discovered evidence of oxidative damage to the DNA and lipids of biopsy samples from the vastus lateralis muscles of ME patients. They also found an increase in the activity of antioxidant enzyme systems, including glutathione peroxidase, an increase they suggest is a compensatory measure in response to oxidative stress.
A group at Dundee found extensive damage to the cardiovascular system, which showed severe oxidative stress in the endothelium leading to swelling and stiffening. More recently, a post-mortem examination of a person who died from myalgic encephalomyelitis found nothing wrong until the spinal cord was examined, where severe inflammation was found.
It is clear that the major underlying themes of ME are viral (or bacterial) infections, a hyperactive immune systems and oxidative stress.
If diet has any role in ME treatment it would be to reduce oxidative stress and inflammation in addition to perhaps aid the immune system.

Treatments
A common «treatment» of ME is cognitive-behavioral therapy (CBT). The therapy is based on an assumption that ME is in part a mental issue rather than that of a physiologic defect. The goal of CBT is to provide the patient with coping strategies rather than being a treatment.
Also graded exercise therapy (GET) has been a popular choice of “treatment”. This also is not a treatment, but is used to decrease loss of muscle mass and function caused by the forced sedentary lives of ME patients.
Cognitive behavior therapy and/or graded exercise therapy are primarily recommended to people with mild or moderate ME. Studies among the ‘‘25% group’’, whose members have severe disabling ME, the people that are often bed-bound, found that more than 90% of its members were dissatisfied with cognitive behavioral therapy and graded exercise therapy.

From Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. M. Hooper, J Clin Pathol 2007 60: 466-471.
I can only imagine what it must feel like to have a body that refuses to cooperate only to have someone telling you to get your act together and start exercising. 
The evidence for positive effects of GET/CBT is not strong. Some reports have found little or no effect with CBT, whereas GET is often found to be harmful. Some researchers hypothesize that the exercise induced oxidative stress in addition to the already high level of oxidative stress is one of the reasons for the negative effect of exercise.
In a recent review article, Twisk and Maes stated that, “CBT/GET is not only hardly more effective than non-interventions or standard medical care, but many patients report that the therapy had affected them adversely, the majority of them even reporting substantial deterioration.
A 2008 Cochrane review found that 40% of patients reported improvements in fatigue after cognitive behavioral therapy compared with 26% in usual care at the end of treatment. At follow-up, 1-7 months after treatment ended, when people who had dropped out were included, there was no significant difference between the two groups. The results are far from promising.
In a rather uncommonly harsh but quite likely fair tone the authors conclude that, “… it is unethical to treat patients with ME/CFS with ineffective, non-evidence-based and potentially harmful «rehabilitation therapies», such as CBT/GET.

Drugs
In ME as in many other conditions and diseases it seems that medication is only ameliorating symptoms without doing anything about the actual problem. To be fair though, the causes of ME have not been identified so treatment programs are obviously directed at symptom relief.
One drug type used is TNFa inhibitors. This group of drugs has been shown to lead to improvement in patients with rheumatoid arthritis, Crohn’s disease, psoriasis and other diseases. One unpublished pilot study used the TNFa inhibitor etanercept and found a considerable benefit in the treatment of six patients with ME.

ME as a metabolic disease
When considering ME it seems a condition characterized by a sort of “last drop” mechanism. It seems too many factors work together to overpower the system causing a shut down. These factors include viral infections, stress (psychological or physiological), oxidative stress, hormonal disturbances and others.
Considering this, it is not unlikely that diet may be one of the factors pushing the body over the edge. It is thus also likely that diet may ameliorate symptoms or aid recovery.
In a case-control study, Maloney et al (2010) found that persons with ME were twice as likely to have metabolic syndrome compared with healthy controls. There was also a significant relationship between the number of metabolic syndrome factors and ME. Each additional factor was associated with a 37% increase in likelihood of having ME. Among persons with ME, the number of metabolic syndrome factors was significantly correlated with worse fatigue.
In order to elucidate the relationship between ME and lifestyle factors a Dutch group examined 247 patients with ME. Surprisingly (to some) those with ME were found to lead a healthier lifestyle compared to the general Dutch population. Compared with the general Dutch population, significantly fewer ME patients were overweight. Significantly more female CFS patients abstained from alcohol, and fewer male ME patients smoked. This makes me think that the stress of trying to live healthy lives (or being an over achiever) might even be a causative factor. 
However, questionnaires were used to assess fat, fiber, fruit and vegetables and we know how the story goes. Fruits, fibers and vegetables are considered healthy while fat is considered unhealthy.

As far as I can see, no conclusive data have been found on correlations between diet and ME. However, considering the pathophysiology of ME, there is one type of diet that compared to other diets seem an obvious choice.
Low carbohydrate diets have been shown to reduce markers of inflammation and reduce oxidative stress far better that comparative diets. In addition there are data indicating high levels of omega 3 fatty acids might help reduce inflammation. I´ll leave the omega 3 to omega 6 ratio discussion to others.
I am looking forward to the first trial where ME patients are put on low carbohydrate (hopefully also high fat) diets.