Excerpt: A summary of the suggested underlying pathophysiologies and treatment approaches
By Dr. Andrew J. Wright, MBChB, DRCOG, MRCGP, DCH, DIHom
Editor’s Note: the following is an excerpt from Dr. Wright’s complete report.
I have written this document in order to share information with colleagues and
patients. It is a technical paper but I hope to produce a lay readership version as soon as time allows. My experience in this field is based on more than 10 years of treating a large number of patients in primary care, general medical out-patient clinics, and in private practice. I am one of the Medical Advisors to Action for ME, a charity involved in helping patients and their caregivers. I also sit on the research group of that charity. The charity has recently financed a literature and evidence search to obtain as much information as is currently available about this group of illnesses. I have collaborated in that research. I was also a member of the Reference Group of the Chief Medical Officer’s Working Group on Chronic Fatigue Syndromes.
Organic vs. Psychiatric Model
I am a firm advocate of the organic basis for these illnesses. I feel the
psychiatric/psychological models of the illnesses are incomplete and unable to explain the underlying pathophysiology. I fully accept that psychological difficulties arise in these illness, but only at the same frequency as in any other chronic illness. I also accept that psychological/psychiatric type interventions can help those patients who are in need of them.
Antidepressants may help pain. They can alleviate depression, where it exists, and increase a sense of well being. Some patients derive good benefit
from cognitive behavioral therapy (CBT), if psychological problems co-exist with their illness. I encourage CBT in those who are in need of it.
Some studies do show that a sub-group benefit from graded activity, but only when experts in the field administer that treatment. Others studies show no sustained improvement and high drop out rates. However, many of these studies are based on the Oxford Criteria, where the only essential requirement for inclusion is fatigue. This is different from the 1994 CDC criteria that requires many more of the wide range of symptoms you commonly find in patients.
The best advice is often to do less, not more. Giving general advice to simply increase aerobic exercises incrementally often makes people worse. Exercise capacity is reduced. This is partly secondary to an inability to achieve maximal predicted heart rate. This is thought to be due to autonomic dysfunction. It is interesting how often people who are so ill that they look
as though they should be in a hospice, are told to ‘pull themselves together and go for a walk’. Surely, we have all been taught to recognize when somebody is ill. Just because they are, 'Paper Perfect People,' i.e., all our standard tests come back normal, doesn’t mean we should disbelieve them. It is possible of course that we may not have done the right tests. I believe the evidence set out below shows this to be largely true.
I feel the reasons for the dominance of the psychiatric model is complex. Nonetheless, it is due in part to a way of thinking that has been practiced by doctors for centuries.
Patient: attends with a set of problems.
Doctor: doesn’t understand and /or cannot help with the patient’ s problems.
Solution: make the patient the problem and then you can forget about their difficult problems.
Although this is a simplification and might appear too rhetorical it does often happen. Secondly is the lack of information readily accessible about the organic basis of the illness. Many of the research articles are published in journals that are not normally read outside the researchers own specialty. This is one of the problems in disseminating information about this group of illnesses. It is very difficult to get articles published in the more popular journals, unless they have a psychological bias.
As a consequence patients are then often referred on to psychological services. This is not fair to the majority of patients, or the psychiatrists/psychologists who are busy enough.
Unfortunately, the overwhelming acceptance of this model has led to patients' needs being largely ignored by the Health and Social Services. This in many circumstances is the most difficult problem that patients face. Not only do they have to suffer from the illness, but are disbelieved by the Medical and Social Service professions and often suffer great financial hardship. I am sure that this was never the intention of those people who proposed the psychiatric model of this illness, but that is what has happened.
Interestingly, psychiatrists working in this field are becoming more cautious these days about labeling this as a purely functional illness. They accept that the underlying pathologies are not yet completely defined. They also caution about misdiagnosis. In a recent paper by Deale and Wesseley, it was said that on review of patients attending a Chronic Fatigue clinic around 68% of those with a psychiatric diagnosis had been incorrectly labeled. There was no evidence of past or present psychiatric disorder.
Also around 35% had psychiatric disorders that had gone unrecognized. Therefore the use of scales such as the Hospital Anxiety and Depression ratings are advised. This figure of around a third with problems correlates well with any chronic illness.
In order to understand this group of illnesses, an awareness of some of the newer specialties, such as Neuroendocrinoimmunolgy, Chronobiology, Toxicology and Integrative Medicine has been important in formulating these ideas. Some of the more controversial ideas emerging in medicine are also described. You will not find the answers in your undergraduate textbooks! The 'one disease, one diagnosis, one drug approach,' does not apply with this group of illnesses.
The evidence set out below is not comprehensive, partly because there has been an exponential rise in research recently, which can only be good news for sufferers. However this also this means that any overview is out of date almost immediately after it has been completed. Up to date though, charities, or individuals have paid for most of the research. Central funding has been negligible.
Immunology and Toxicology
Some of the more striking abnormalities are those found in the 2-5 Synthetase/RNase L anti-viral pathway. These are not specific to CFS/ME though, and abnormalities can occur in other viral illnesses. This pathway works as follows: viruses activate the 2-5- synthetase enzyme. This in turn converts ATP into 2-5 oligoadenylate and activates the RNase L enzyme, which degrades viral and single stranded RNA. Various Protein kinase enzymes also becomes activated and elevated, which again inhibits both viral replication and protein synthesis. It has been suggested that environmental toxins in
the presence of heat shock proteins can also activate this pathway.
Dr. Robert Suhadolnik, at Temple University, showed as far back as 1989, that activity in this pathway was upregulated in patients with chronic fatigue syndromes. Crucially in 1996 it was also noted that a proportion of patients had an abnormal version of the RNase L enzyme. This low molecular weight form is 37kDaltons, compared with the normal 80 and 47 kDalton versions. It was thought initially that all chronic fatigue patients had this abnormal form.
The most recent figures I could find by Dr. K De Meirleir showed that the low molecular weight version was found in 680 out of 705 patients. The levels quantitatively vary though, and the amounts correlate with the Karnofsky Disability Index. The low molecular weight RNase L enzyme is up to six times more biologically active and resists protein degradation. Therefore when expressed, patients suffer an even greater depletion of ATP reserves and
inhibition of protein synthesis. It has been suggested that mycoplasma genus cause the splitting of Rnase L.
The overwhelming fatigue with an acute viral illness is due in part to ATP depletion in order to fuel anti-viral pathways.
Unfortunately, to test for this enzyme requires blood to be sent on dry ice to Belgium at present. Interestingly studies have shown that those suffering from Fibromyalgia do not express the low molecular weight RNase L. If confirmed by larger studies this would be a major difference between the two illnesses.
This upregulated system, either expressing RNase L or low mol wt RNase L can then cause problems to varying degrees with enzymatic detoxification pathways, particularly in the liver. It can monopolise protein synthesis and deplete essential nutrients such as glutathione. Low white cell glutathione is a feature of treatment resistant patients.
Some very interesting and important work has come from Professor Vojdani, in California. In 1998 he published a paper which showed that RNase L inhibitor, the controlling enzyme in the 2-5 Synthetase/RNase L pathway, is low in CFS/ME patients. This may be the underlying problem. The reason this occurs is not yet known.
Vojdani suggests that measurements of RNase L inhibitor and Protein Kinases can be used to show a viral etiology and monitor relapses and remissions. Measurements of Protein Kinase 1 are very important in studying the mechanism of interference with signal transduction in lymphocytes. This signal transduction system consists of eleven different isoenzymes, each having different biological actions, and distinct abnormalities can be seen in CFS/ME patients. Also important is measuring NK cell activity, which is often low.
Other evidence on the importance of this upregulation and expression of the abnormal enzymes has come from the use in patients of the agent Ampligen, also called poly (1)-poly (C12U). This is a synthetic, mismatched double-stranded RNA with potent anti-viral and regulatory properties. In a double blind study involving 92 patients, measures of clinical response such as cognitive functioning, exercise ability and less reliance on other medications, improved in 80% of sufferers. The Karnofsky scale was used in this study to measure the physical and social ability. Although rather
simplistic, it provides a useful functional guide.
Ampligen is best given early in the illness, and in those positive for low molecular weight RNase L. Not only does it have potent anti-viral properties, it is also an immune system modifier, i.e. an allosteric modifier. It can downregulate an activated immune system, as in CFS/ME, and upregulate a depressed immune system, as in AIDS patients. Unfortunately Ampligen is expensive, around £6-8000 per treatment. It also has to be given IV twice a week. Relapses can occur on completing treatment and repeat courses may be necessary.
Another interesting study by Vojdani, published in 1999, showed that not only could viruses elevate the above anti viral pathway, but so could environmental pollutants, particularly Methyl Tertiary Butyl Ether, (MTBE), and Benzene, components of petrol fumes. Obviously many people are exposed to these toxins on a daily basis. He had already shown that workers in the petroleum industry have toxicity problems, especially high levels of apoptosis of cells. He took two groups of patients with CFS /ME- 20 with viral genomes present on PCR testing, but no history of chemical exposure or sensitivities, and 20 with significant exposure to MTBE and benzene, but
no viral genomes on PCR testing.
In the same paper, Vojdani also showed that through the use of MDBK cell lines, anti-Interferon-beta inhibited viral induction of the antiviral pathways by 90%, but only 40% in chemical induction. Whereas anti-Heat shock protein 70 inhibited 90% of chemical induction, but only 20% of viral induction. This suggests that proinflammatory cytokines are implicated in viral induction, and heat shock proteins in chemical induction.
A further study that looked at pro-inflammatory cytokines showed that in a retrospective cross-sectional study, there was a significant increase in serum TNFalpha, compared to controls (p<0.0001). This raises the possibility of the use of TNF-alpha-blockers, such as those introduced recently for Colitis.
These are chimeric anti-TNF-alpha antibodies, e.g. the monoclonal antibody ’Infliximab’. It is interesting that in a study by Dr Buskila, out of 113 patients with inflammatory bowel disease, 49% of Crohns disease patients and 19% of Ulcerative Colitis patients satisfied the diagnostic criteria for Fibromyalgia. Similar approaches are being tested in Rheumatoid Arthritis. Maybe we can turn off the illnesses in their early stages, before too much damage has been done.
Another Vojdani study investigated the cell death rates in patients with CFS/ME. The study looked at the induction of apoptosis in peripheral blood lymphocytes of CFS/ME patients and controls, by the growth inhibitory cytokine Interferon-Alpha. The apoptosis rate in patients was 26.6% n=29, compared to controls 9.9% n= 15. This is similar to workers with increased apoptosis secondary to environmental toxins.
A further toxicology study by Dunstan showed that the amount of organochlorines in sufferers was unusually high. He took patients and people who had been exposed to organochlorines with similar clinical features. However, being exposed to chemicals means that this group are excluded from the standard CDC diagnostic criteria for CFS/ME.
Whilst talking about chemicals, it is interesting to note that about 20-47% of CFS/ME and Fibromyalgia sufferers complain of severe multiple chemical sensitivities. About 4-6% of the general population also has severe chemical intolerance. The levels of chemicals needed to trigger these problems would normally be considered to be non toxic, however, host factors involving sensitization/amplification of endogenous responses seem to be to blame. Chemicals can sensitize the Limbic system directly via the Olfactory nerve. The Limbic system then sends efferent messages to the hypothalamus and the mesolimbic dopaminergic pathway.
Research to date has shown that these sensitized pathways react unfavorably with exposure to volatile organic compounds and pesticides, facilitating behavioral, autonomic, endocrine and immune function dysfunction. This is seen by sensitizability of cardiovascular parameters, resting EEG alpha-wave patterns, betaendorphin levels and impairment of divided-attention task performance. This fits in well with Professor Behan’ s work. It shows that people exposed chronically to low dose organophosphates, who also have CFS/ME, exhibit a neuroendocrine profile identical to acutely exposed people. An example would be farm workers with 'sheep dip flu.' Here the results of investigations looking at serotonin, acetylcholine and brain glucocorticoid steroid receptor activity were identical in OP exposed workers and
those with CFS/ME.
What are the most effective treatment protocols to date? Having collaborated with Michelle Ranaghan, Action for ME’ s former Research Officer, on the large literature search, I have read a lot of studies. I feel the studies, with the fewest side effects and prolonged results on follow up, are those using Integrated Medicine Protocols.
Crucially all the problems identified above are treated simultaneously. Treatment is not only with conventional drugs, but also with hormones, antioxidants and minerals, herbal preparations, nutritional advice and sensible guidelines on rest and activity. Psychological problems are also addressed.
One of these was by Dr. Jacob Teitelbaum who published an open study showing promising results and followed this up with a very well constructed double blind placebo controlled trial, which has now been accepted for publication in the Journal of Chronic Fatigue Syndrome. I feel this approach would be the easiest to apply on the NHS.
72 Fibromyalgia patients, 70 of whom also fulfilled the CDC criteria for CFS, were divided into two groups and treated either with placebo therapies or active treatment by a unified, simultaneous approach for three months. Patients were treated based on clinical symptoms and/or lab testing for:
1. Subclinical thyroid, adrenal (cortisol and DHEA), and gonadal hormone imbalances or deficiencies.
2. Disordered sleep (Zolpidem,Trazadone, Amitriptyline, Clonazepam, Melatonin or herbs such as Valerian root).
3. Suspected neurally mediated hypotension with fludrocortisone and increased
4. Opportunistic infections, e.g., common parasites such as Blastocystis hominis, Giardia and Dientamoeba, Clostridia, and fungal overgrowth with conventional antimicrobials and herbs.
5. Suspected nutritional deficiencies (multivitamins, magnesium glycinate/malic acid, B12 and Iron). 32 patients in each group completed the study. Using a combination of patient and physician assessments, FMS Impact questionnaire, Analogue scores and Tender Point Indices, the results were, with p< 0.0001
The conclusion was that significantly greater benefits were seen in the treatment, as opposed to placebo group, for all primary outcomes. After one year, improvements had been maintained in the treated group. Further details can be found at http://www.endfatigue.com
The second impressive study was by Professor Majid Ali. This was an Open prospective study on 150 Fibromyalgia/CFS/ME patients. The study was based on the results of clinical, biochemical and video microscopy findings. The program involved nutritional education, intravenous and oral nutritional supplements, redox restoring substances, such as glutathione and taurine, hormonal support, probiotic and herbal bowel therapies, nasal and other oxidative therapies, gentle stretching and noncompetitive exercise, and training in self-regulation and stress reduction. No attempt was made to limit the number of therapies patients received. Neither was any attempt
made to blind the study, as this would have been impossible to do, given the
comprehensive and holistic therapies involved.
The patients were divided into three groups according to duration of illness:
Group 1 < 3 years
Group 2 3- 6 years
Group 3 > 6 years
In conclusion, we have direct evidence from good sources that these groups of syndromes share common factors, and that there is proof for their organic basis.
In CFS/ME) it seems that we should see this as an illness probably caused by enteroviruses, acting on a body that is for many reasons already stressed biologically, with high pre-morbid levels of oxidative stress, resulting in high peroxynitrite levels.
Other biological stressors may be the cause or add to this, such as IAG or these may be mechanical, dietary, environmental, physical, infective or psychological.
What seems important is that the blood-brain barrier becomes permeable allowing viral entry. Treatments should be aimed at identifying and removing these stressors This then could allow neurotropic viruses to cause the hypothalamic and other downstream hormone effects. There also exists a chronically activated immune system, which may result from the initial insult or co-existent microbial, or toxin overload or a combination of the two. It seems that there is over-expression of aberrant RNA, derived initially from an enterovirus, protected by a viral type coat which in the presence of LMWRNase L leads to extreme ATP depletion.
Does the body feel that it is being constantly infected by an enterovirus? Pollution and vaccines have been suggested as a cause for the loss of control of HERV associated mRNA production. Following this hypercoagulability develops, causing problems in both blood and lymph microcirculation’ s. This hypercoagulability may arise from a combination of hereditary, immune mediated and oxidative stress pathways. We have chronic sympathetic system activation, from many causes.
We then have a situation where the body is subject to a high degree of oxidative stress, probably the most damaging state in biology. I feel Fibromyalgia is mainly an illness of oxidative stress associated with spinal problems as outlined above. Multiple subtle endocrine changes are also present in the CFS/ME/FM complex, both quantitatively in terms of hormone levels, and also qualitatively, with loss of circadian rhythmicity.
Given the bi-directional flow of information between the nervous, endocrine and immune systems, we are presented with a perfect example of Chaos Biology. This results in a failure of homeostasis and homeodynamics. Simply stated, a body that cannot respond to any form of biological stress, be it environmental, infective, physical or psychological.
Although some of the ideas I have presented are novel and controversial, I believe the overall hypothesis has a sound base in science. We must remember that all explanations for these groups of illnesses are at present speculative. However, the studies demonstrating pathophysiology are not and neither are the results of treatment programs.
I am afraid that as a profession, it seems we have shot ourselves in the foot again, and have assumed psychological causation, because of our lack of knowledge. Medical history is littered with illnesses that were thought to be psychogenic, e.g., Tuberculosis, epilepsy and Hypothyroidism. We need to act quickly to repair the damage and work for funding for patients on the NHS.
© 2002 Dr. Andrew John Wright. The preceding is an excerpt. To read this report in its entirety, please visit: http://www.cfsresearch.org/cfs/research/treatment/36nf.htm