The Hummingbirds' Foundation for M.E.

The Hummingbirds' Foundation for M.E. (HFME) is fighting for the recognition of M.E.,
and for patients to be accorded the same basic human rights as those with similar
disabling and potentially fatal neurological diseases such as M.S.

An important note:

Before reading the research/advocacy information given in the links below, please be aware of the following facts:

1. Myalgic Encephalomyelitis and ‘Chronic Fatigue Syndrome’ are not synonymous terms. The overwhelming majority of research on ‘CFS’ or ‘CFIDS’ or ‘ME/CFS’ or ‘CFS/ME’ or ‘ICD-CFS’ does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all ‘CFS’ labelled research as ‘only relating to ‘CFS’ patients’ (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that ‘CFS’ is just a ‘watered down’ definition of M.E. and that M.E. and ‘CFS’ are virtually the same thing and share many characteristics.

A very small number of ‘CFS’ studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The
A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy paper is recommended reading and includes a checklist to help readers assess the relevance of individual ‘CFS’ studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.

In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of ‘CFS’ must be abandoned.

2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.

Enteroviral and post-polio research

For more information see also: The outbreaks (and infectious nature) of M.E. 



The Nightingale Definition of Myalgic Encephalomyelitis (M.E.)
by Dr Byron Hyde 2006

Preface

Since the Nightingale Research Foundation's publication in 1992 of its textbook, The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, there has been a tendency by some individuals and organizations to assume that M.E. and CFS are the same illness. Over the course of two International Association of Chronic Fatigue Syndrome (IACFS, formerly the American Association of CFS) conferences, there have been suggestions that the name CFS be changed to M.E., while retaining the CFS definitions as a basis for such change. This does not seem to me to be a useful initiative: it would simply add credence to the mistaken assumption that M.E. and CFS represent the same disease processes. They do not.

M.E. is a clearly defined disease process. CFS by definition has always been a syndrome

At one of the meetings held to determine the 1994 U.S. Centers for Disease Control and Prevention (CDC) definition of CFS, in response to my question from the floor, Dr. Keiji Fukuda stated that numerous M.E. epidemics he cited the Los Angeles County Hospital epidemic of 1934, the Akureyri outbreak of 1947-48 and the 1955-58 Royal Free Hospitals epidemics-- were definitely not CFS epidemics. Dr. Fukuda was correct.

[Contains details of the many absnormalities seen in M.E., and explains how these can be tested for.]


The effects of CBT and GET on patients with Myalgic Encephalomyelitis looks at the physical effects of CBT and GET on patients with M.E. From HFME

This essential feature of M.E. is characterised by a unique form of paralytic muscle weakness whereby muscles perform normally to begin with but after even a minor degree of physical effort; three, four or five days, or longer, elapse before full muscle power is restored. This is quite distinct from the ‘chronic fatigue’ seen in many other illnesses.

Fatigue’ and feeling ‘tired all the time’ are not at all the same thing as the very specific type of paralytic muscle weakness or muscle fatigue which is characteristic of M.E. (and is caused by mitochondrial dysfunction) and which affects every organ and cell in the body; including the brain and the heart. This causes – or significantly contributes to – such problems in M.E. as; cardiac insufficiency (a type of heart failure), orthostatic intolerance (inability to maintain an upright posture), blackouts, reduced circulating blood volume (and pooling of the blood in the extremities), seizures (and other neurological phenomena), memory loss, problems chewing/swallowing, episodes of partial or total paralysis, muscle spasms/twitching, extreme pain, problems with digestion, Raynaud’s phenomenon, vision disturbances, breathing difficulties, and so on. These problems are exacerbated by even trivial levels of physical and cognitive activity, sensory input and orthostatic stress beyond a patient’s individual post-illness limits leaving M.E. patients extremely disabled (Bassett 2009, [Online]).

People with M.E. are experiencing a form of heart failure which can be exacerbated by even relatively low levels of activity. Many patients are housebound and bedbound and often are so ill that they feel they are about to die.  Some M.E. patients do die due to overexertion. People with M.E. would give anything to instead only be severely ‘fatigued’ or tired all the time.

Fatigue or post-exertional fatigue (or malaise) may occur in many different illnesses such as various post-viral fatigue states or syndromes, Fibromyalgia, Lyme disease, and many others – but what is happening with M.E. patients is an entirely different (and unique) problem of a much greater magnitude. These terms are not accurate or specific enough to describe what is happening in M.E.

The paralytic muscle weakness seen in M.E. affects all muscles including the heart and causes what is commonly known as exercise intolerance; that patients relapse with excessive physical and cognitive exertion, as well as with orthostatic stress. These features are a core part of what M.E. is as they are responsible for causing much of the symptomatology and disability associated with the disease (Hyde 2006, [Online]) (Hooper 2006, [Online]) (Hooper & Marshall 2005a, [Online]) (Hyde 2003, [Online]) (Dowsett 2001, [Online]) (Hooper et al. 2001, [Online]) (Dowsett 2000, [Online]) (Dowsett 1999a, 1999b, [Online]) (Dowsett 1996, p. 167) (Dowsett et al. 1990, pp. 285-291) (Dowsett n.d., [Online]).

Doctors who have experience with M.E. (and can tell the difference between authentic M.E. and various unrelated fatigue states) and the leading M.E. experts all concur; physical, cognitive or orthostatic overexertion can have many harmful effects on patients both in the short- and long-term. The following comments which illustrate this point are provided by some of the world’s leading M.E. experts, all of whom have been specialising in M.E. for many years and each of whom has seen literally thousands of M.E. patients;

 

1. Dr Melvin Ramsay, a UK doctor who specialised in M.E. for more than thirty years, from the Royal Free Hospital M.E. outbreak of 1955 until his death in 1990, and who is credited with having written some of the most accurate description of the illness to date, explains, ‘The degree of physical incapacity varies greatly, but the [level of severity] is directly related to the length of time the patient persists in physical effort after its onset; put in another way, those patients who are given a period of enforced rest from the onset have the best prognosis. Those who are given complete rest from the onset do well. Those whose circumstances make adequate rest periods impossible are at a distinct disadvantage, but no effort should be spared to give them the all-essential basis for successful treatment. Since the limitations which the disease imposes vary considerably from case to case, the responsibility for determining these rests upon the patient. Once these are ascertained the patient is advised to fashion a pattern of living that comes well within them’ (Ramsay 1986, [Online]).

 

2. Dr. Elizabeth Dowsett explains, ‘There is ample evidence that M.E. is primarily a neurological illness although non neurological complications affecting the liver, cardiac and skeletal muscle, endocrine and lymphoid tissues are also recognised. Apart from secondary infection, the commonest causes of relapse in this illness are physical or mental over exertion. The prescription of increasing exercise is such a situation (or in the early stage of the illness when the patient desperately needs rest) can only be counter-productive’ and ‘This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory’ and ‘The prescription of increasing exercise can only be counter-productive.’

Also from Dr Elizabeth Dowsett:

The brain has often been likened to a computer. However, there are fundamental differences in its essential function of processing, comparing and storing information. Unlike a computer, which can be switched on and off and is programmed to give set answers to a single question, the chemical transmitter bridging the synapse introduces a variability into the on-going message and "Neuronal Plasticity" into the receiving/transmitting network. It has been shown that similar modifications in response may be induced by virus infection. The brain contains some 100 billion neurons connected to some 10,000 relay stations and this enormous electrical activity creates a massive need for energy, using up 20% of the entire body's demand for oxygen and glucose. Recent studies of the brain stem by SPECT scan, indicate hypoperfusion and low metabolic activity in subjects with M.E.

Modern research indicates disturbed metabolism in many areas essential to motor control in the brain stem of patients with M.E., the majority of whom have evidence of inco-ordinated muscle twitching after slight exertion.

A good memory demands normal functioning of almost all areas of the cerebral cortex, the basal nerve centres of the mid brain (eg the thalamus and hippocampus) and their interconnecting pathways through the brain stem. Fluctuations of metabolic activity in these areas (often made worse by physical and mental [overexertion]) have been reported in SPECT scans of patients with M.E., the vast majority of whom complain of difficulty with short-term memory (n.d.c, [Online]).

Dr Dowsett states about M.E. patients that, ‘20% have progressive and frequently undiagnosed degeneration of cardiac muscle which has led to sudden death following exercise.’

According to Dr. Elizabeth Dowsett, any M.E. patient can also be stopped from deteriorating further and at least stabilised (if not in time experiencing some level of improvement) through receiving appropriate care and being allowed to get the needed level of rest (providing that the patient has not already been exposed to unrecoverable levels of overexertion) (Dowsett & Ramsay et al. 1990) (Dowsett 2000, [Online]) (Dowsett 2001a, [Online]) (Dowsett n.d.b., [Online]). Dr. Elizabeth Dowsett also explains that:

Scientific discoveries recently reported, indicate that embryonic stem cells left over from foetal development, remain in the brain tissue during adult life and are capable of “running repairs” (thus patients are able to recover after head injury, stroke and relapse in ME). However, overuse of these repairs, as in ME (when the patients are overstressed [overexexerted] physically or mentally) will cause unnecessary deterioration which may then become irreparable. Intervention in the form of financial, rehabilitation and nutritional support can do much to prevent the physical, occupational and other deterioration in the quality of life for a large group of patients now between 40 and 60 years of age, to say nothing of educational loss in children.

     HEALTH SERVICE INTERVENTIONS: It is sad to read that these are said to be of dubious priority in the present state of the NHS when it is known that the correct type of rehabilitation can stabilise the illness. This requires access to local facilities without discrimination against patients with a diagnosis of ME, together with a domiciliary nursing service for the bed-bound who are unable to travel ( 2002b, [Online]).

 

3. Dr Byron Hyde explains in his M.E. textbook that it has been found that those patients with M.E. who returned to work soon after becoming ill or while they were still seriously or severely ill – instead of having an extended period of rest and recovery – are at risk of causing an abnormal increase in damage ‘to a heart muscle already vulnerable and under attack from an acute viral infection’ and that those who do not, or cannot, rest in the early stages of M.E. potentially create ‘a physical injury to the myocardium, cardiac pacemaker cells or their autonomic control.’ Dr Hyde explains that:

This is not just clinical supposition, there is a strong basic for this belief of work or exercise potentiated heart damage in the literature. It is well known that enteroviruses may cause chronic cardiac disease as well as major neurological injury. Kandolf states that "enteroviruses are capable of causing dilated cardiomyopathy of sudden onset or lead to a variety of common arrhythmias." Utilizing mouse models, Wilson and again Reyes demonstrated that Coxsackie infected [enterovirus infected] mice, forced to swim to the point of exhaustion during the acute phase of infection, developed chronic heart disease whereas Coxsackie infected mice who were allowed to rest during the acute phase, did not develop chronic heart disease.

M.E. represents a possibility of serious cardiac injury primarily in patients who exercise or maintain exhaustive work efforts during the onset of their illness. It is possible that some of these patients who die and other that develop major cardiac changes are never recognised as M.E.

With both CNS and CVS disease, chronicity may be provoked by maintaining strenuous exercise and work levels.. Early patient activation may represent serious cardiovascular danger to patients [with M.E.]. The strange concept of waiting 6 months to diagnose a classical case of M.E. [brought about by the confusion between M.E. and ‘CFS’] is unnecessary and fraught with potential danger to the patient. Such a diagnostic delay may create legal consequences for the physician. Physicians who take an early aggressive approach in physically activating these acute stage patients may do so at both their and their patient’s peril (Hyde & Jain 1992a, pp. 375-383).

M.E. is an infectious neurological disease and represents a major attack on the central nervous system (CNS) by the chronic effects of a viral infection. The world’s leading M.E. experts, namely Ramsay, Richardson, Dowsett and Hyde, (and others) have all indicated that M.E. is caused by an enterovirus. (This also includes doctors such as A. Gilliam, W.H. Lyle, Elizabeth Bell of Ruckhill Hospital, James Mowbray of St Mary’s, and Peter Behan). The evidence which exists to support the concept of M.E. as an enteroviral disease is compelling (Hyde 2007, [Online]) (Hyde 2006, [Online]).

Dr Hyde explains that enteroviral infections are able to cause:

  1. a chronic host infection
  2. major or no cardiac disease depending on the virulence of the subtype
  3. cardiac injury dependent upon the sex of the patient and of the level of physical activity of the patient during the acute or infectious stage
  4. cardiac disease depending upon the immunological variability of the host (Hyde & Jain 1992a, p. 40).

An enterovirus would also explain the; age variation, sex variation, obvious resistance of some family members to the infection and the effect of physical activity (particularly in the early stages of the illness) in creating more long-term/severe M.E. illness in the host (Hyde & Jain 1992a, p. 40). There is also the evidence that; M.E. epidemics very often followed polio epidemics, M.E. resembles polio at onset, serological studies have shown that communities affected by an outbreak of M.E. were effectively blocked (or immune) from the effects of a subsequent polio outbreak, evidence of enteroviral infection has been found in the brain tissue of M.E. patients at autopsy, and so on (Hyde 2007, [Online]) (Hyde 2006, [Online]) (Hyde 2003, [Online]) (Dowsett 2001a, [Online]) (Dowsett 2000, [Online]) (Dowsett 1999a, 1999b, [Online]) (Hyde 1992 p. xi) (Hyde & Jain 1992 pp. 38 - 43) (Hyde et al. 1992, pp. 25-37) (Dowsett et al. 1990, pp. 285-291) (Ramsay 1986, [Online]) (Dowsett & Ramsay n.d., pp. 81-84) (Richardson n.d., pp. 85-92) (Richardson 1999, [Online]).

Dr Byron Hyde, also explains that the vascular and cardiac dysfunctions seen in M.E. are often the most obvious set of dysfunctions when looked for, and are the cause of a significant number of M.E. symptoms:

The subject of vascular pathology is not new. The fact of the children dying of a Parkinsonian-like vascular injury to the basal ganglia in Iceland during the Akureyri M.E. Epidemic is an obvious indication of the CNS vascular effects in M.E. Vasculitis has been well documented by Dr. E. Ryll in his description of the epidemic in the San Juan Mercy, Sacramento California Hospital in 1975. He described this M.E. epidemic as an epidemic vasculitis. He was correct. Following my 21 years of examining M.E. patients and 16 years of subjecting M.E. patients to brain imaging techniques, it has become obvious to me that we are dealing with both a vasculitis and a change in vascular physiology. Numerous other physicians have supported this finding.

The recent interpretation of the cause of Multiple Sclerosis (MS), as an injury of the microvasculization causing the injury of the schwann cells that in turn causes the demyelination injuries of MS has been added to that of paralytic poliomyelitis as an essential vascular injury. Paralytic poliomyelitis was thought to be a primary injury to the anterior horn cells of the spinal cord but is now recognized as a vasculitis injuring the circulation to the anterior horn cells. Poliomyelitis is generally a non-progressive, specific site injury, although post-polio syndrome with demonstration of subcortical brain changes has challenged that belief. MS is a recurrent more fulminant physiological vascular injury. M.E. appears to be in this same family of diseases as paralytic polio and MS. M.E. is definitely less fulminant than MS but more generalized. M.E. is less fulminant but more generalized than poliomyelitis. This relationship of M.E.-like illness to poliomyelitis is not new and is of course the reason that Alexander Gilliam, in his analysis of the Los Angeles County General Hospital M.E. epidemic in 1934, called M.E. atypical poliomyelitis (2007, [Online]).

Dr Byron Hyde also writes, ’I have some M.E. patients with a circulating red blood cell volume less than 50% of expected and a very large number with the range of 60% to 70%. What this test means is that blood is pooling somewhere in the body and that this blood is probably not available for the brain. When blood flow to the heart decreases sufficiently, the organism has an increased risk of death. Accordingly, the human body operates in part with pressoreceptors that protect and maintain heart blood supply. When blood flow decreases, pressoreceptors decrease blood flow to noncardiac organs and shunt blood to the heart to maintain life. This, of course, robs those areas of the body that are not essential for maintaining life and means the brain, muscles, and peripheral circulation are placed in physiological difficulty.’ This physiological difficulty is exacerbated by physical and mental activity and orthostatic stress.

Dr Byron Hyde goes on to say that, ‘In MRI spectography of arm muscle of M.E. patients, it has been shown that because of an abnormal buildup of normal metabolites, the muscle cell actually shuts down to prevent cell death.’ Dr Hyde explains that this is what is happening to the true M.E. patient’s cell physiology in the brain, and in muscle as a result of certain levels of physical and mental activity; there is ‘cell field shutdown’ to prevent the death of the cell (Hyde 2003, [Online]).

Dr Byron Hyde explains in The Nightingale Definition of M.E. that,

Possibly due to the fact that some Fibromyalgia patients can be improved by a gradual increase in exercise, or possibly due to the so called protestant ethic that all you have to do to get better is to take up your bed and walk, some physicians have extended the concept of passive or forceful increased exercise to Myalgic Encephalomyelitis patients. This is a common and potentially dangerous, even disastrous misconception. If the M.E. patient conforms to the guidelines set out in this definition, the insurance company can only make the patient worse by instituting progressive aggressive forced physical and intellectual activity. M.E. is a variable but always, serious diffuse brain injury and permanent damage can be done to the M.E. patient by non-judicious pseudo-treatment (2007, [Online]).


A New and Simple Definition of Myalgic Encephalomyelitis and a New Simple Definition of Chronic Fatigue Syndrome & A Brief History of Myalgic Encephalomyelitis & An Irreverent History of Chronic Fatigue Syndrome by Dr Byron Hyde 2006

‘Do not for one minute believe that CFS is simply another name for Myalgic Encephalomyelitis (M.E.). It is not. Though CFS is based upon a typical M.E. epidemic, in my opinion it has always been a confused and distorted view of reality. The invention of Chronic Fatigue Syndrome has to be one of the most curious cases of inventive American scientific imperialism that one could imagine. It is my opinion that the CDC 1988 definition of CFS describes a non-existing chimera based upon inexperienced individuals who lack any historical knowledge of this disease process. The CDC definition is not a disease process.’

[Contains details of the many absnormalities seen in M.E.]


The Impact of Persistent Enteroviral Infection by Dr Elizabeth Dowsett

By 1972, a distinguished group of clinicians and scientists had set out to share information, form research groups and hold national and international conferences related to the problems of ME. Following successful vaccination against the three polio viruses during the early 1960s over 60 epidemics of atypical, non paralytic polio had been recorded in the UK alone. It was obvious that (since Nature abhors a vacuum) the non polio enteroviruses were naturally filling the gap(6), and demonstrating their potential for inducing a serious neurological disease of considerable chronicity, mainly affecting school children and middle aged adults in the most important and productive years of their lives. Most of the famous London teaching hospitals were involved, at that time in investigating epidemics and in subsequent research while links were forged with international institutions in USA, Canada, Europe and Australasia, facing the same problems.

Research first published in 1975(7) indicated that the enteroviruses (which triggered the illness) belonged to a vast group of viruses (many of them at that time yet to be discovered) which were able to survive persistently in the human body as an uncoated form of intracellular genetic material, thus avoiding direct challenge from the immune system. Simple (indirect) laboratory confirmation of their presence based on blood tests, was available in most NHS laboratories without let or hindrance, while the European enterovirus reference centre at Ruchill Hospital in Glasgow, provided expert identification. It was clear from their work that epidemics occurred at 10 year intervals and pandemics (world wide spread) were approximately 20 years apart. By 1987, famous research workers, including Drs Ramsay, Richardson and (from Canada and the USA) Byron Hyde and David Bell, Professors Mowbray and Banatvala and scientists of the status of Len Archard and (from the USA) Roger Loria and Richard Bruno and Nancy Frick, were able to enlighten and to back up the hundreds of GPs and NHS consultants dealing with an ever increasing number of seriously disabled patients. The potential of this disease to disable children and interrupt their education was realised(8) and (in the early 1980’s) the late effects of polio were rediscovered (earlier reports dated from the late 19th century).


The Complexities of Diagnosis  by Dr Byron Hyde 2003

(Taken from: Handbook of Chronic Fatigue Syndrome by Leonard A. Jason, Patricia A. Fennell and Renée R. Taylor)

The physician and patient alike should remember that CFS is not a disease. It is a chronic fatigue state as described in four definitions starting with that published by Dr. Gary Holmes of the CDC and others in 1988 (Holmes, Kaplan, Gantz, et al., 1988; Holmes, Kaplan, Schonberger, et .al., 1988). The definition created by Lloyd, Hickie, Boughton, Spencer, and Wakefield (1990) is also widely used in Australia. There are two subsequent definitions. The Oxford definition of 1991 (Sharpe et al., 1991) and the 1994 NIH/CDC definitions (Fukuda et al., 1994) are basically, with a few modifications, copies of the first definition. Where the one essential characteristic of ME is acquired CNS dysfunction, that of CFS is primarily chronic fatigue. By assumption, this CFS fatigue can be acquired abruptly or gradually. Secondary symptoms and signs were then added to this primary fatigue anomaly. None of these secondary symptoms is individually essential for the definition and few are scientifically testable. Despite the list of signs and symptoms and test exclusions in these definitions, patients who conform to any of these four CFS definitions may still have an undiagnosed major illness, certain of which are potentially treatable.

Although the authors of these definitions have repeatedly stated that they are defining a syndrome and not a specific disease, patient, physician, and insurer alike have tended to treat this syndrome as a specific disease or illness, with at times a potentially specific treatment and a specific outcome. This has resulted in much confusion, and many physicians are now diagnosing CFS as though it were a specific illness. They either refer the patient to pharmaceutical, psychiatric, psychological, or social treatment or simply say, "You have CFS and nothing can be done about it."

[Contains details of the many absnormalities seen in M.E., and explains how these can be tested for.]


Time to put the exercise cure to rest? by Dr Elizabeth Dowsett

There is ample evidence that M.E. is primarily a neurological illness. It is classified as such under the WHO international classification of diseases (ICD 10, 1992) although non neurological complications affecting the liver, cardiac and skeletal muscle, endocrine and lymphoid tissues are also recognised. Apart from secondary infection, the commonest causes of relapse in this illness are physical or mental over exertion 1. And, on follow up over decades (rather than weeks or months), the average person so disabled is found to be functioning (as a student, employee or parent for example) dangerously near their energy limits. The prescription of increasing exercise is such a situation (or in the early stage of the illness when the patient desperately needs rest) can only be counter-productive.

[In other words - YES!]


The Late Effects of ME by Dr Elizabeth Dowsett

"The number likely to be affected by the post-polio syndrome has been calculated as between 200-270/100,000 currently[7], but no account has been taken of survivors from non-paralytic polio which could easily double that figure. Possible costing for ME support has been based on 3 times the cost of maintenance for multiple sclerosis on the supposition that ME is 3 times as common[4]. The only costs that we can be sure of are those derived from the failure of appropriate management, and of inappropriate assessments which waste vast sums of money and medical time while allowing patients to deteriorate unnecessarily.[16]

Research workers must be encouraged and appropriately funded to work in this field. However they should first be directed to papers published before 1988, the time at which all specialised experience about poliomyelitis and associated infections seem to have vanished mysteriously![11,12,13]"


*O* PRESS RELEASE: From: The Department of Neurology ,Institute of Neurological Sciences, Glasgow University 1992, Dr Behan

Introduction

The Chronic Fatigue Syndrome (known in the United Kingdom an Myalgic Encephalomyelitis or Postviral Fatigue Syndrome) is a relapsing illness which occurs in epidemics and sporadically.It in now being recognized worldwide and is of apparent increasing prevalence. It's main clinical feature is overwhelming fatigue, made worse by exercise and cited associated with a wide variety of other symptoms including sleep disturbances, muscle aches and pains;, atypical depression, difficulties with concentration and with memory, and symptoms of gastrointestinal upset.

We, in this unit, have had a particular interest in the syndrome and have studied It over the past 15 years or more- We have been able to detect clinically a relationship between the onset of this illness and viral infection, the viral infection being most commonly with Enteroviruses. This possibility that Enteroviruses might be involved
in this disorder has long been suspected particularly because of the relationship of previous epidemics of the syndrome to that of poliomyelitis outbreaks. Recent studies have shown that patients with the syndrome may excrete enterovirus in stool, and preliminary investigations detected enterovirus specific RNA sequence. in samples
of muscle biopsies from patients in which a fifth were found to be positive using a nucleic hybridisation technique. We extended these studies using the highly sensitive polymerase chair reaction and demonstrated that it was possible to examine for low copy numbers of viral nucleic acid sequences in cells and tissues from patients. The technique was applied to muscle biopsies where 53% of patients were found to be positive and their muscle cells to contain enteroviral RNA sequences.

NEW DATA TO BE REPORTED:

We will report at the 1st International Research Conference on Chronic Fatigue Syndrome to be held at Albany, New York, 2 - 4 October 1992, our new findings relating particularly to Enteroviral infection. We have now extended our PCR data to now cover hundreds or patients together with controls and have continued to find a very significant proportion of the patients' muscle biopsies to contain enterovirus on PCR. In addition, we have used several different types of enteroviral primers and have obtained Identical result; in the patients with these primers; the control muscle biopsies from healthy subject; and patient; with other muscle diseases being entirely negative. We furthermore have isolated RNA from patients and probed this with large enterovirus probes which demonstrated that full length 7.4 kilobase virus was present in these patients. Indeed, detailed studies including Northern Blot Analysis showed that the material was true virus, as did specific studies implying antibody to enterovirus as an aid to augmentation to electronmicroscopy. Furthermore, this virus was shown to be replicating normally at the level of transcription. Sequence analysis of this isolated material showed that it had 80% homology with coxsackie B viruses and 76% homology with Poliomyelitis virus, demonstrating beyond any doubt that the material was enterovirus. We were able to extend these studies; in a unique way by being able to study post mortem material from a definite case of Chronic Fatigue Syndrome who died as a result of drug overdose. This showed that Enterovirus was present in skeletal muscle in, heart muscle, but particularly was abundant in brain. Detailed studies of the brain enterovirus revealed that it was most prevalent in diencephalic particularly hypothalamic, regions.


*O* Three Babuska Clusters of Enteroviral-Associated Myalgic Encephalomyelitis by Byron Hyde MD

Although physicians associated with Nightingale have been studying both M.E. and CFS patients since 1984, it was only in 1995 that we began to include in the investigation of each new Nightingale M.E. patient, an evaluation by PCR for chronic persisting enteroviral infection. The material employed was frozen blood serum that was evaluated by the research team of the viral laboratory of Ruchill Hospital in Glasgow. These patients were re-evaluated approximately once or twice a year for a period of three years. Blood serum from control patients of similar age and sex were submitted with serum from M.E. patients. Blood from other patients with various autoimmune diseases or neurological illnesses were also submitted along with our samples. The names were changed in repeat samples. The serum received at Ruchill Hospital was divided into reserves and two blinded samples of this serum were investigated by PCR in different laboratories. Only when each sample source was found to be positive for the same enteroviral code was the serum accepted as having a specific circulating enterovirus.


Are Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Synonymous Terms? by Byron Hyde MD

Enterovirus infections have an incubation period identical to incubation periods noted in most of the M.E. epidemics, that is, of 4-6 days.


*O* The impact of persistent enteroviral infection by Dr Elizabeth Dowsett

By 1972, a distinguished group of clinicians and scientists had set out to share information, form research groups and hold national and international conferences related to the problems of ME. Following successful vaccination against the three polio viruses during the early 1960s over 60 epidemics of atypical, non paralytic polio had been recorded in the UK alone. It was obvious that (since Nature abhors a vacuum) the non polio enteroviruses were naturally filling the gap(6), and demonstrating their potential for inducing a serious neurological disease of considerable chronicity, mainly affecting school children and middle aged adults in the most important and productive years of their lives. Most of the famous London teaching hospitals were involved, at that time in investigating epidemics and in subsequent research while links were forged with international institutions in USA, Canada, Europe and Australasia, facing the same problems.


*O* Research into ME - 1988-1998 Too much PHILOSPHY and too little BASIC SCIENCE! by Dr Elizabeth Dowsett

Virology finally emerged from the dark ages of technical difficulty in which viral infection could be guessed at but seldom proved.  From 1948, when tissue culture permitted some viruses to be grown, electron-microscopy enabled others to be seen and the techniques of molecular biology permitted virtually all microbes to be studied (by the amplification and identification of their genetic fragments, even if hidden in internal body organs) the sequence of events in related diseases such as poliomyelitis and ME became clear.  During an outbreak of polio and ME in the 1950s, isolation of a whole range of polio and non polio enteroviruses from clinical and asymptomatic patients, indicated that there were some 69 related viruses in this group associated with a wide range of common acute and chronic infections of children and adults including paralytic poliomyelitis (mainly but not exclusively caused by polioviruses) and with acute viral meningitis, encephalitis, myocarditis, Epidemic Bornholm Disease and Hand Foot and Mouth Disease, infections of the middle ear, skin and eye, to say nothing of chronic myocarditis Juvenile onset diabetes, Myalgic encephalomyelitis and other chronic neurological and motor neurone conditions, caused by a wide range of non polio enteroviruses (Coxsackie, ECHO and enterviruses 68-71)(5).  Echo 9 virus was actually isolated from patients during an outbreak of ME in Lancashire during the 1955-56 epidemic years(6.).  The rediscovery of the Post-Polio Syndrome (first described in 1870) but brought to the attention of doctors in the USA by patient sufferers one hundred years later, indicated that the polio viruses could persist silently for some 25-40 years after the initial infection. 


Enterovirus related metabolic myopathy: a postviral fatigue syndrome. Lane RJ, Soteriou BA, Zhang H, Archard LC.Division of Clinical Neurosciences and Psychological Medicine, Imperial College, London SW7, UK. r.lane@imperial.ac.uk

OBJECTIVE: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients. METHODS: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points. RESULTS: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus. CONCLUSIONS: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.


Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach John kai-sheng Chia 1* and Andrew Y Chia 11 EV Med Research, United States. To whom correspondence should be addressed.
E-mail:
chiasann@pol.net.

J Clin Pathol. Published Online First: 13 September 2007. doi:10.1136/jcp.2007.050054 Copyright 2007 by the BMJ Publishing Group Ltd & Association of Clinical Pathologists.

Abstract

Aims The aetiology for chronic fatigue syndrome remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, we evaluated the presence of viral capsid protein 1(VP1), Enterovirus RNA and culturable virus in the stomach biopsies of CFS patients.

Methods165 consecutive CFS patients underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using enterovirus-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus. RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA-later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for enterovirus.

Results135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (P <0.000001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from 6 patients at the onset of the CFS/abdominal symptoms, and 2-8 years later demonstrated positive staining in the paired specimens. EV RNA was detected in 9/24 (37 %) paraffin-embedded biopsy samples, and 1/21 controls had detectable EV RNA (p<0.01). 1/3 patient had detectable EV RNA from two samples taken 4 years apart. 5 patient samples demonstrated transient growth of non-cytopathic enteroviruses.

Conclusion Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsies of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsies.

Discussion:

"An estimated 80 - 90% of our 1400 CFS patients have recurring gastrointestinal symptoms of varying severity, and epigastric and/or lower quadrant tenderness by examination, compared to only 3/100 control subjects (authors unpublished observations). Finding enterovirus VP1 protein in 82% of stomach biopsy samples seems to correlate with the high percentage of CFS patients with GI complaints."

"Finding enteroviral protein in some of the control subjects could be explained by the high prevalence of enterovirus infections throughout the year, affecting as many as 50 million Americans per year, or 17-25% of the population.4 Viral shedding in stool can persist for weeks after acute infections. It is probable that the control subjects had an asymptomatic or self-limited enterovirus infection within the preceding months. More careful screening of the control subjects may increase the specificity of this test in future studies."

"Enterovirus infection initiated the GI symptoms and CFS, and the persistence of the virus years later likely was responsible for the patients symptoms."

"Endomyocardial biopsy taken from patients with viral myocarditis demonstrated persistence of enteroviral genome in almost one-third of the samples 1 year after acute infection.31 Muscle biopsy specimens taken from CFS patients, and postmortem examination of brain tissues from one CFS patient, years after the initial infection, also demonstrated the persistence of enteroviral genome.69 32 Collectively, these findings clearly support the concept of viral persistence in human tissues."

"Taken together, the findings of enteroviral protein, RNA and the growth of non-cytopathic viruses in the stomach tissue of CFS patients, years after initial infection, suggest a strong association between enteroviral persistence/infection and CFS."

"By inference, a significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which can lead to diffuse symptomatology without true organ damage. If confirmed, stomach biopsies could be used as a test to document viral persistence, and serve as an objective means to follow the response to antiviral therapy, in addition to quantitation of subjective complaints."


Journal of Clinical Pathology 2005;58:1126-1132; doi:10.1136/jcp.2004.020255 © 2005 by BMJ Publishing Group Ltd & Association of Clinical Pathologists

REVIEW The role of enterovirus in chronic fatigue syndrome J K S Chia Correspondence to: Dr J K S Chia CEI Research Center, 23560 Crenshaw Blvd 101, Torrance, CA 90505, USA; Chiasann@pol.net

PDF

ABSTRACT Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. Observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.

DISCUSSION
Taken together, these data suggest that enterovirus can initiate and perpetuate the immunological response often seen in patients with CFS. Smouldering viral infection of various cells of the body with continuous expression of double stranded RNA and viral antigens could result in a chronic inflammatory state in the local tissues and account for the diverse symptoms reported by these patients.

The mechanism of viral persistence reconciles the two seemingly opposing observations of the past two decades: absence of live virion in chronically infected patients and animals and the finding of enteroviral RNA in the blood or other tissues. The finding of double stranded RNA is consistent with the clinical symptoms of patients with CFS. Without forming double stranded RNA, our patients with HIV or hepatitis B/C infections are usually not symptomatic, even though the measurable viraemia often exceeds 104–106/ml. In contrast, patients with CFS and the presence of viral RNA in peripheral blood leucocytes or in tissues, but without true viraemia, have debilitating symptoms; the severity of the symptoms correlated with the frequency of finding enteroviral RNA in the peripheral blood leucocytes (J Chia and A Chia. Detection of double-stranded RNA in the peripheral blood leukocytes of patients with the chronic fatigue syndrome. Abstract T-101. In: Program of the 104th General Meeting for the American Society of Microbiology. New Orleans: Louisiana, 2004). In most of the patients with CFS, the cyclic nature of low grade febrile illness and severe exacerbation after physical activity would be consistent with a cyclical pattern in the viral replicative activity.

It is probable that viral RNA found inside cells, in a stable double stranded form, can dissociate and replicate using viral RNA replicase; some of the positive strands, although restricted in replication,51 are translated to viral proteins during active metabolic states (for instance, exercise), which subsequently perpetuates the immunological response, including but not limited to synthesis of specific neutralising antibody. Consistent with this hypothesis, a recent study on Sjögren’s syndrome clearly detected enteroviral RNA and VP1 protein in minor salivary gland biopsies from these patients, but not in controls.52 From the available data in the literature, however, it is not possible to exclude with complete certainty the possibility that a few virions are actually formed and sequestered in membrane vesicles within the infected human cells.

Among other immunostimulatory effects, double stranded RNA is a potent inducer of interferon synthesis, which activates intracellular RNase, with resultant degradation of excessive single stranded RNA. The finding of a higher level of RNase L activity in the mononuclear cells of patients with CFS is consistent with this paradigm.53,54 However, enough positive and negative strands probably recombine to form stable double stranded RNAs, which are resistant to RNAse L inactivation, and the life cycle will start again when the pressure of the immune response decreases. Ironically, the continuing inflammatory response towards persistently infected cells/tissues to halt viral infection may be partially responsible for the difficulty in finding viral genomes in these patients, and may also be responsible for the symptoms.

Take home messages

  • A severe flu-like illness occurs in most cases of chronic fatigue syndrome (CFS), suggesting that an infection triggers and possibly perpetuates this syndrome

     

  • Common viral infections and unusual causes of CFS could be diagnosed based on the details of the initial flu-like illness, if present, epidemiological history, and early virological testing

     

  • Different laboratories from Europe and recently from the USA have found enteroviral RNA in the tissues, including peripheral blood mononuclear cells and muscles, of patients with CFS

     

  • Viral persistence through the formation of stable double stranded RNA reconciles the two opposing observations of the past two decades: (1) the absence of live virion in chronically infected patients and animals and (2) the presence of enteroviral RNA in the blood or other tissues

     

  • Smouldering viral infection of various cells with continuous expression of double stranded RNA and viral antigens could result in a chronic inflammatory state in the local tissues, accounting for the diverse symptoms

     

  • Interferon {alpha} and {gamma} act synergistically against enterovirus in vitro, and preliminary studies suggest that this combination may be an effective treatment for patients with chronic enteroviral infection

     

Self replicating double stranded RNA molecules (replicons) have been well studied and are currently used as vectors for DNA vaccines and drug susceptibility assays.55,56 Double stranded RNAs can be extremely potent adjuvants for immune responses or, alternatively, these molecules with certain sequences may silence our genes by blocking our mRNA,57 although the evidence for this last mechanism is not yet available for CFS.

"Ironically, the continuing inflammatory response towards persistently infected cells/tissues to halt viral infection may be partially responsible for the difficulty in finding viral genomes in these patients, and may also be responsible for the symptoms"

The paradox remains, however, that despite an ongoing immune response, these viral RNA infected cells are not eradicated. It is possible that viruses hide in long living, immunologically privileged cells, including but not limited to, macrophages, muscles, myocardial cells, and neurones,28–37 although these cells are unable to produce much live viruses, perhaps, in part, because of the pressure from local interferon and high concentrations of neutralising antibody—a form of cryptic infection. Viral antigen has been identified in tissues by virus specific monoclonal antibodies but positive staining did not allow the differentiation between membrane bound viral proteins and sequestered virions.58,59 Persistent infection of B cells and monocytes/macrophages, the cells initially responsible for the uptake/transport of virus, has been well described for other intracellular pathogens.60 Recently, we have found enteroviral RNA in the bone marrow samples of two patients with CFS and cyclic neutropenia (JK Chia, unpublished observation, 2004), suggesting that stem cells in the bone marrow could be a source of ongoing viral infection, as reported in animal models of enteroviral infection.59

Thus, renewed interest is needed to study further the role of enterovirus as the causative agent of CFS. Many aspects of this research need to be addressed but there are three urgent priorities.

(1) To overcome the technical difficulties associated with the enteroviral RNA detection assay, because a reliable and reproducible measurement of cell associated viral RNA will provide a marker for antiviral treatment and provide conclusive evidence of chronic infection.

(2) To perform a proof of concept, randomised, double blinded, placebo controlled clinical trial investigating the efficacy of the combination of interferon {alpha} and {gamma}.

(3) To develop inhibitors for viral RNA replicase, the main mechanism for RNA replication, which allows the persistence of the viral genome in infected cells. In the future, a well designed, randomised, controlled trial of antiviral treatment will ultimately provide crucial information on the pathogenic role of enterovirus in patients with CFS and other chronic diseases.

ACKNOWLEDGEMENTS
The laboratory work was supported by the Chu-Lee Tu memorial research fund.

© 2005 by BMJ Publishing Group Ltd & Association of Clinical Pathologists


From IiME

'Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome  associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiolgy of ME/CFS – an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS.  By analyzing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS.'


*O* Are echoviruses still orphans? Hill WM. Deparment of Microbiology, Basildon Hospital, Nether Mayne, England, UK.

A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.
 

 
*O*  Myalgic encephalomyelitis--a persistent enteroviral infection? Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Basildon Hospital, Essex, UK.

Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances.
 

 
*O*  Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Department of Biochemistry, Charing Cross and Westminster Medical School, London.

Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.
 

Evidence for enteroviral persistence in humans. Galbraith DN, Nairn C, Clements GB. Journal of Genenal Virology 1997; 78(2): 307-12.

Abstract: We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5' non-translated region (bases 174-423) was determined for each amplicon. Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses. In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.


Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Journal of General Virology 1995; 76: 1701-1707.

Abstract: This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.


Enteroviral RNA sequences in muscle in patients with chronic fatigue syndrome. Gow RJ, Behan PO. British Medical Journal 1991; 302: 692-6.

Abstract: OBJECTIVE-To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN-Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING-Institute of Neurological Sciences, Glasgow. SUBJECTS-60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES-Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS-15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS-Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.


Some long term sequelae of Coxsackie B virus. Gray JA. Journal of the Royal College of General Practitioners 1984; 34: 3-6.


Are echoviruses still orphans? Hill WM. British Journal of Biomedicine Science 1996; 53(3): 221-6.

Abstract: A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.


Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Richardson J. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.

Abstract: It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.


Chronic enterovirus infection in patients with postviral fatigue syndrome. Yousef G, Bell E, Mann G, et al. Lancet 1988; 1: 146-50.

Abstract: 76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were no (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive from VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.


Enteroviruses and postviral fatigue syndrome. Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Ciba Foundation Symposium 1993; 173: 146-54.

Abstract: Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.


 
Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome. Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. Department of Neurology, University of Glasgow.

OBJECTIVE--To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN--Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING--Institute of Neurological Sciences, Glasgow. SUBJECTS--60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES--Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS--15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS--Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.
 

 
A study of Coxsackie B virus infections, 1972-1983. Bell EJ, McCartney RA.

The results of a twelve-year study of Coxsackie B virus (CBV) infections in patients with a variety of acute and chronic illnesses are reported. CBVs were isolated from only 123 patients most of whom were children with respiratory illness. Virus diagnosis in adults was based mainly on the detection of significant rising or static high neutralizing antibody titres. Between 1972 and 1979 most investigations centred on patients with suspected viral heart disease, 12% of whom were found to have diagnostically significant CBV titres. In studies on patients with definite myo-pericarditis the number positive increased to 33%. In 1980 clinical interest switched to the possible role of CBV in myalgic encephalomyelitis (ME), an illness of diverse symptomatology. Investigation of suspected cases of ME in 1983 showed that 16% were serologically positive compared to 4% of normal adults in the West of Scotland. In patients with well-documented ME this figure rose to 41%. The demand by clinicians for CBV neutralizing antibody tests has increased over the past twelve years and continues to escalate annually, especially in patients with chronic relapsing illness.
 

 
*O*  Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Regional Virus Laboratory, Ruchill Hospital, Glasgow, UK.

This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.
 

Chronic enterovirus infection in patients with postviral fatigue syndrome. Yousef GE, Bell EJ, Mann GF, Murugesan V, Smith DG, McCartney RA, Mowbray JF. Lancet. 1988. Department of Pathology, St Mary's Hospital Medical School, London.

76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were not (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive for VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.
 

Myalgic Encephalomyelitis - a persistent enteroviral infection? Dowsett E, Ramsay AM, McCartney RA and Bell EJ. Postgraduate Medical Journal 1990; 66: 526-530.

Abstract: Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances.


Post viral fatigue syndrome: persistence of enteroviral RNA in skeletal muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Journal of the Royal Society of Medicine 1988; 81: 326-9.

Abstract: Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.


 
Evidence for persistent enterovirus infection of the central nervous system in patients with previous paralytic poliomyelitis. Muir P, Nicholson F, Sharief MK, Thompson EJ, Cairns NJ, Lantos P, Spencer GT, Kaminski HJ, Banatvala JE. Department of Virology, UMDS St. Thomas' Hospital, London, United Kingdom.

It has been suggested that late onset neurological deterioration after poliomyelitis may be due in some cases to persistent poliovirus infection of the central nervous system. In view of this, we decide to determine whether polioviruses and other enteroviruses can persist in the central nervous system. In a previous study, one of us (M.K.S.) reported serological evidence of persistent poliovirus infection of the central nervous system (CNS) in a proportion of these patients. We have now studied cerebrospinal fluid (CSF) from these patients for the presence of enterovirus RNA sequences using the polymerase chain reaction (PCR). Enteroviral RNA was detected in 3 of 24 patients with a clinical diagnosis of post-polio syndrome, but in none of 36 patients with stable poliomyelitis, and none of 36 patients with other neurological conditions of noninfective origin. All 3 patients in whom viral RNA was detected had high intrathecal levels of poliovirus-specific oligoclonal IgM bands. In a second study we examined formalin-fixed postmortem CNS tissue from 7 patients with a history of paralytic poliomyelitis. Enterovirus RNA was detected in tissue from the spinal cord from 3 patients, but not in the cerebral cortex. We are now conducting a larger prospective, blind study of patients with evidence of late deterioration. Analysis of the first 30 patients studied revealed the presence of enterovirus RNA in CSF of 1 of 4 patients with unexplained late-onset post-polio weakness, 1 of 6 with some evidence of clinical deterioration, but none of 20 without inexplicable signs of post-polio weakness. Enteroviral RNA was also detected in spinal cord from 2 of 3 patients who died from other causes during this study. These studies provide virological evidence that enteroviruses may persist in the CNS of man. Further study is required in order to understand fully the biological and clinical significance of these findings.


[Enterovirus infections in new disguise] [Article in Swedish] Fohlman J, Friman G, Tuvemo T. Infektionskliniken, Akademiska sjukhuset, Uppsala.

Enteroviruses (Coxsackie A and B, echovirus, poliovirus) belong to a group of small RNA-viruses, picomavirus, which are widespread in nature. Enteroviruses cause a number of wellknown diseases and symptoms in humans, from subclinical infections and the common cold to poliomyelitis with paralysis. The development of polio vaccines is the greatest accomplishment within the field of enterovirus research and the background work was awarded the Nobel prize in 1954. New knowledge implies that enteroviruses play a more important part in the morbidity panorama than was previously thought. Chronic (persistent) enteroviruses were formerly unknown. Serologic and molecular biology techniques have now demonstrated that enteroviral genomes, in certain situations, persist after the primary infection (which is often silent). Persistent enteroviral infection or recurrent infections and/or virus-stimulated autoimmunity might contribute to the development of diseases with hitherto unexplained pathogenesis, such as post polio syndrome, dilated cardiomyopathy, juvenile (type 1) diabetes and possibly some cases of chronic fatigue syndrome.
 

Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. The Journal of Medicine 1993; 24(2-3): 145-60.

Abstract: Molecular hybridization using an enterovirus group specific probe detected virus RNA in muscle biopsy samples from 25 of 96 cases of inflammatory muscle disease and similarly from 41 of 158 cases of postviral fatigue syndrome (PFS). Enterovirus RNA was detected in only two of 152 samples of control muscle. The inflammatory myopathy group comprised patients with polymyositis (PM), juvenile dermatomyositis (JDM) or adult dermatomyositis (DM), and all showed the presence of an inflammatory infiltrate and fiber necrosis on histological examination of a muscle biopsy sample. In contrast, muscle samples from the PFS group were histologically normal except for non-specific changes such as occasional single fiber atrophy. By analogy with enteroviral myocarditis, which can progress to a post-inflammatory disease with persistence of virus in myocardium and disposes to the rapid development of dilated cardiomyopathy, we propose that PFS syndrome may be a sequela of a previous inflammatory viral myopathy.


Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Journal of General Virology 1990; 71 (6): 1399-402.

Abstract: A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.


 
Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Department of Biochemistry, Charing Cross and Westminster Medical School, London, U.K.

A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.
 

 
Evidence for enteroviral persistence in humans. Galbraith DN, Nairn C, Clements GB. Regional Virus Laboratory, Ruchill Hospital, Glasgow, UK.

We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5' non-translated region (bases 174-423) was determined for each amplicon. Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses. In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.
 

 
Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Department of Biochemistry, Charing Cross and Westminster Medical School, London.

Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.
 

Coxsackie B viruses and myalgic encephalomyelitis. Bell EJ, McCartney RA, Riding MH. Journal of the Royal Society of Medicine 1988; 81: 329-31.

Abstract: Data collected over the past 6 years suggest that Coxsackie B viruses (CBV) play an important role in myalgic encephalomyelitis (ME). Since psychological upset is a feature of this illness, 247 patients, recently admitted to a psychiatric hospital, were tested for neutralizing antibodies to CBV. A total of 12.5% had significantly raised CBV titres compared with 4-5% of 'well' control groups; the percentage positive was greatest (21%) in those aged 30-39 years. During 1985 and 1986 sera from 290 adults with ME were tested using the newly developed CBV IgM ELISA test; 37% were CBV IgM positive compared with 9% of 500 'well' adult controls. Forty-seven children, with ME were similarly tested during this period; 38% were positive, implying recent or active CBV infection. The combined use of this ELISA test and the virus probe techniques now available should further help to elucidate the exact role of CBV in this disabling illness.


 
How enteroviruses might evade the immune system. Cunningham et al. J  Gen Virology, 1990, 71, 1399
 

*O* Redefinitions of ME - a 20th Century Phenomenon by Dr Elizabeth Dowsett
 
Advantages of the “polio-like” description – general awareness of the entity by physicians; information readily available in standard text books and medical journals.  Supportive evidence:  (a)  a virological distinction between the 2 diseases was not available until the development of virus culture in 1948.  This resulted in the discovery of some 69 related polio and non-polio enteroviruses.  Although the majority of host/virus contacts produce subclinical infections, these agents are extremely versatile with a wide range of overlapping tissue affinities.  They are reliably associated with many acute infections of the respiratory and intestinal tracts;  with middle ear, neurological, skin, muscle, throat and mucous membrane infections; with epidemics of viral meningitis, Bornholm and Hand Foot and Mouth disease and with chronic sequelae affecting the brain, heart muscle, the pancreas and other endocrine glands.  (b) Serological studies in Iceland, following the introduction of oral polio vaccine in 1958, indicated that a 1948 epidemic of Iceland Disease (ME) in the north of the island effectively blocked a 1957 epidemic of polio type I in the south from spreading north.  At the same time the response to polio type I oral vaccine was standard in the south but aberrant in patients who suffered from the 1948 epidemic in the north.  This indicated a close relationship between the agents of both diseases with competition for receptor sites in the bowel and persistence of the 1948 epidemic agent over 7 years.

 
Elevated Plasma Prolactin and EEG Slow Wave Power in Post-Polio Fatigue: Implications for a Dopamine Deficiency Underlying Post-Viral Fatigue Syndromes Richard L Bruno, Susan Creange, Jerald R Zimmerman and Nancy M Frick HarvestCtr@AOL.COM Journal of Chronic Fatigue Syndrome 1998 vol.4 no.2 page 61-75
 
To test the hypothesis that plasma prolactin and electroencephalographic (EEG) slow wave activity are correlated with fatigue, 33 polio survivors without medical or psychologic comorbidities were studied. Subjects were administered the Post-Polio Fatigue Questionnaire (PFQ) and had resting measurement of both plasma prolactin and bilateral temporal-occipital power across the EEG frequency spectrum. Typical daily fatigue severity on the PFQ was significantly correlated with daily difficulty with attention, staying awake and motivation, but not with measures of acute polio severity or the number of limbs affected by late-onset Post-Polio Sequelae symptoms. Prolactin was significantly correlated with daily fatigue severity on the PFQ (r = .39; p <0.5). EEG power was equal between the two hemispheres across all frequency bands. However, EEG slow wave power in the right hemispheres was significantly correlated with daily fatigue severity and prolactin level (r = .37; p <.05). Using multiple linear regression, age at acute polio, frequency of difficulty with attention on the PFQ, prolactin and right hemisphere slow wave power predicted 72% of the variance of the daily fatigue severity rating (r = .85; p < .0001). These data suggest that increased prolactin secretion and EEG slowing are related to the severity of post-polio fatigue, findings similar to those in patients with acute paralytic and non-paralytic poliomyelitis and with chronic fatigue syndrome. A primary role is suggested for a dopamine deficiency (versus serotonergic receptor supersensitivity) underlying impaired cortical activation and the symptoms associated with putative post-viral fatigue syndromes.


Chronic fatigue syndrome--aetiological aspects  Dickinson CJ  Wolfson Institute , St. Bartholomew's & Royal London School of Medicine & Dentistry, London, UK. Eur J Clin Invest 1997 Apr;27(4):257-67 (ISSN: 0014-2972)

"Regional blood flow studies by single photon-emission computerized tomography (SPECT) have been more consistent. They have revealed blood flow reductions in many regions, especially in the hind brain. Similar lesions have been reported after poliomyelitis and in multiple sclerosis--in both of which conditions chronic fatigue is characteristically present. In the well-known post-polio fatigue syndrome, lesions predominate in the RAS of the brain stem. If similar underlying lesions in the RAS can eventually be identified in CFS, the therapeutic target for CFS would be better defined than it is at present. A number of logical approaches to treatment can already be envisaged".


Thu, 15 Feb 2001 "Dr. Richard L. Bruno"
CFSENG@AOL.COM

I have received some questions as a result of my recent post to Co-Cure on CFS vs PPS and OPV which I thought might be of interest to the Co-Cure readers. Question: "What, specifically, was it from Sabin's 1947 data that suggests that some of the people with ME/CFS may be survivors of nonparalytic polio? Are there research reports available online?" Answer: They are not available on line. I went through the Sabin Archive in Cincinnati. Take a look at the non-paralytic polio papers and the "Parallels" between polio and CFS paper at: http://members.aol.com/harvestctr/pps/lib2.html Question: "And what about those people who developed the disease as teenagers in the 1990s (and who weren't around in the 1950s)? If any of them have NPP, would they have contracted it from the older patients, or from vaccines, or from some other source?" Answer: They would not have had polio at all. If a virus caused their CFS, it would have been from some other source. Our best guess as a cause is another enterovirus very similar to the poliovirus, e.g., Coxsackie B4, that can cause brain and spinal cord lesions identical to those caused by the poliovirus. Polio only means gray in Latin, referring to damage to unmyelinated neurons. Poliovirus causes "polio," but so do other viruses, e.g., Enterovirus 71 causing "polio" in Brazil. Question: "Is there a way to test for NPP in today's patients?" Answer: You can do an EMG, where needles are inserted into muscles, to look for "silent" denervation. But EMG can give false negatives even in polio survivors. We have found MRI and hormonal correlates of PPS fatigue but they are identical to the findings s in CFS! Question: "Would vaccine programs in place since the 1950s have given everyone so many antibodies to polio that such testing would be futile?" Answer: Probably. By if one had a "natural" poliovirus infection their antibody titre might be higher than if they only had the vaccine. Hope this helps! Dick Bruno


Poliovirus induces an early impairment of mitochondrial function by inhibiting succinate dehydrogenase activity.Koundouris A, Kass GE, Johnson CR, Boxall A, Sanders PG, Carter MJ School of Biological Sciences, University of Surrey, Guildford, Surrey, United Kingdom. PMID: 10814509, UI: 20275463

Poliovirus infection of COS-1 and T47D cells caused a rapid decrease in total cell respiration, and this was attributed to an inhibition of mitochondrial respiration. The stimulation of mitochondrial respiration by pyruvate plus malate or succinate was impaired in saponin-permeabilised cells. However, this inhibition could be overcome by the addition of N,N,N',N'-tetramethyl-1, 4-phenylenediamine and ascorbate. The activity of succinate dehydrogenase was impaired in parallel with the inhibition of mitochondrial respiration during poliovirus infection. This shows that mitochondrial function is profoundly altered during poliovirus infection and that this occurs primarily through inhibition of electron flow at complex II of the mitochondrial respiratory chain. Copyright 2000 Academic Press.



The Plenocoral Trial by Dr Betty Dowsett


Post viral fatigue syndrome: persistence of enteroviral RNA in skeletal muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Journal of the Royal Society of Medicine 1988; 81: 326-9.

Abstract: Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.


Enteroviruses and postviral fatigue syndrome. Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Ciba Foundation Symposium 1993; 173: 146-54.

Abstract: Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.


Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. The Journal of Medicine 1993; 24(2-3): 145-60.

Abstract: Molecular hybridization using an enterovirus group specific probe detected virus RNA in muscle biopsy samples from 25 of 96 cases of inflammatory muscle disease and similarly from 41 of 158 cases of postviral fatigue syndrome (PFS). Enterovirus RNA was detected in only two of 152 samples of control muscle. The inflammatory myopathy group comprised patients with polymyositis (PM), juvenile dermatomyositis (JDM) or adult dermatomyositis (DM), and all showed the presence of an inflammatory infiltrate and fiber necrosis on histological examination of a muscle biopsy sample. In contrast, muscle samples from the PFS group were histologically normal except for non-specific changes such as occasional single fiber atrophy. By analogy with enteroviral myocarditis, which can progress to a post-inflammatory disease with persistence of virus in myocardium and disposes to the rapid development of dilated cardiomyopathy, we propose that PFS syndrome may be a sequela of a previous inflammatory viral myopathy.


Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue. Clements GB, McGarry F, Nairn C, Galbraith DN. Journal of Medical Virology 1995; 45(2): 156-61.

Abstract: The serum of 88 chronic fatigue patients was screened for enteroviral specific sequences by polymerase chain reaction (PCR) assay. The PCR method used was "nested" PCR targetting the 5' nontranslated region of the enteroviral genome which yielded a final fragment length of 264 base pairs. Samples were obtained from patients during 1990-1991. In addition, buffy coat specimens and stool specimens were examined in some patients. Samples from two cohorts of comparison individuals were also obtained. The comparison groups were firstly, acutely ill individuals with symptoms consistent with a presumed enteroviral infection (matched by age, sex, and date of receipt of specimen) and secondly, healthy individuals (matched by age and date of receipt of specimen). Enteroviral specific sequences were detected in 36 of 88 serum samples from chronic fatigue patients, 22 of 82 acutely ill individuals, and 3 of 126 healthy individuals. The enteroviral PCR positivity did not correlate with any one particular feature of chronic fatigue nor did it reflect any history of illness at onset of fatigue, duration of fatigue, or age of patient. These results provide new evidence for the presence of enteroviral specific sequences in serum, buffy coat, and stool samples in many patients with chronic fatigue. This may reflect a persistent enterovirus infection in a proportion of chronic fatigue patients.


Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Journal of General Virology 1990; 71 (6): 1399-402.

Abstract: A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.


Evidence for enteroviral persistence in humans. Galbraith DN, Nairn C, Clements GB. Journal of Genenal Virology 1997; 78(2): 307-12.

Abstract: We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5' non-translated region (bases 174-423) was determined for each amplicon. Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses. In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.


Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Journal of General Virology 1995; 76: 1701-1707.

Abstract: This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.


Enteroviral RNA sequences in muscle in patients with chronic fatigue syndrome. Gow RJ, Behan PO. British Medical Journal 1991; 302: 692-6.

Abstract: OBJECTIVE-To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN-Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING-Institute of Neurological Sciences, Glasgow. SUBJECTS-60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES-Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS-15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS-Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.


Are echoviruses still orphans? Hill WM. British Journal of Biomedicine Science 1996; 53(3): 221-6.

Abstract: A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.


Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Richardson J. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.

Abstract: It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.


Chronic enterovirus infection in patients with postviral fatigue syndrome. Yousef G, Bell E, Mann G, et al. Lancet 1988; 1: 146-50.

Abstract: 76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were no (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive from VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.


CFS May Be Result of Childhood Non-paralytic Polio Infection A layperson-accessible introductory article on this subject by Dr. Richard Bruno appears on-line at www.polionet.org/pen&ink/PI33-Sum00.htm#Childhood in "Pen and Ink," an E-zine of the Polio Experience Network.

Some excerpts and notes:
"A childhood poliovirus infection may cause chronic fatigue in baby-boomers concludes a paper published in the January, 11, 2000, issue of the American Journal of Physical Medicine and Rehabilitation "Paralytic Versus 'Non-Paralytic' Polio: A Distinction without a Difference," by Dr. Richard L. Bruno, director of The Post-Polio Institute at New Jersey's Englewood Hospital and Medical Center and chairperson of the International Post-Polio Task Force."  Dr. Bruno notes that L. Jason's recent CFS prevalence study, published in the October 11, 1999 issue of Archives of Internal Medicine (available on-line at:
www.archinte.ama-assn.org/issues/v159n18/full/ioi90161.html), found that baby-boomers have a higher incidence of CFS:
"Potentially half of those diagnosed today with CFS may in fact have had Summer Grippe or undiagnosed non-paralytic polio as children in the years before the polio vaccine became available," said Dr. Bruno. "They may also have brain activating system damage that causes chronic fatigue [syndrome]."


*O* The Late Effects Of M.E. - Can they be distinguished from the Post-Polio Syndrome? by Dr Elizabeth Dowsett

"The number likely to be affected by the post-polio syndrome has been calculated as between 200-270/100,000 currently[7], but no account has been taken of survivors from non-paralytic polio which could easily double that figure. Possible costing for ME support has been based on 3 times the cost of maintenance for multiple sclerosis on the supposition that ME is 3 times as common[4]. The only costs that we can be sure of are those derived from the failure of appropriate management, and of inappropriate assessments which waste vast sums of money and medical time while allowing patients to deteriorate unnecessarily.[16]

Research workers must be encouraged and appropriately funded to work in this field. However they should first be directed to papers published before 1988, the time at which all specialised experience about poliomyelitis and associated infections seem to have vanished mysteriously![11,12,13]"


*O* A Rose By Any Other Name by Dr Elizabeth Dowsett

Both the earliest definition (HOLMES et al, 1988) and its revision (FUKUDA, 1994) elevated tonsillitis, glandular enlargement and fatigue to unreal importance while overlooking the characteristic encephalitic features of the genuine illness.  These mistakes also inflated the possibility of a psychiatric diagnosis, leading to the incorporation of such a heterogeneous population of psychiatric and non-psychiatric causes later on, that research groups of different persuasions were unable to compare results or evaluate treatment.

The tools we can use today to study the brain offer possibilities which were unimaginable 50 years ago2.  These include Molecular Biology: for example PCR – a microbiological technique capable of amplifying and identifying minute fragments of viral genes, hidden away in internal organs (such as brain, heart or muscle 3) while a test for rapid diagnosis (within five hours) is currently available.  These tests indicate that viruses from the polio group, or related to it, are involved both in the late effects of ME and the Post Polio Syndrome 4.  Brain Imaging: the use of CT, MRI, SPECT and PET scans clearly indicates that metabolic dysfunction in the brain stem and the spinal nerve radiations which transverse it, are initially associated with viral (inflammatory) damage and are the major cause of the cardinal symptoms of ME – central fatigue, stress induced weakness, autonomic nervous dysfunction and the breakdown of homoeostasis over hormonal and other vital functions5.


National ME / FM Action Network's 1st Annual Symposium on Parallels Between Post-Polio Sequelae, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. June 15, 2002

Dr. Dowsett believes that the polio vaccine made room for other polio-like viruses (from the family of viruses called enteroviruses) to take over. According to Dr. Dowsett's research and other work, these other viruses may even hit some parts of the brain harder than in polio, judging by the brain fatigue and research on the ME/CFS brain. So, even if people with ME/CFS don't have paralysis and get as physically weak as people who had polio, they may be even more impaired in other ways. This has VERY IMPORTANT implications for assessment of disability and for treatment.

Important Treatment Information Dr. Bruno says pacing, NOT cognitive behavioural therapy and NOT graded exercise, is the cornerstone of treatment for people with PPS and ME/CFS. The key message is that people with ME/CFS and PPS have demonstrated brain stem dysfunction. This explains a multitude of symptoms because the brain stem controls so many physical and mental processes. Dr. Dowsett supports this view As the Canadian Newsletter `Quest` reports, both Dr Dowsett`s and Dr Bruno`s presentations are amazing, Dr Dowsett tells of her work throughout the years on ME/CFS linking it up with the Post Polio Sequelae. Dr Bruno, himself a paraplegic after Polio, is admirable in his determination to get over to people the effects of PPS, ME/CFS. and what can be done to allow people to help themselves improve their quality of life.


Pleconaril - A New Drug For Enteroviral Infections by Dr Elizabeth Dowsett

If the American multicentre placebo controlled randomised trial of  PLECONARIL in neonatal disease is successful, what a chance we have to treat, stop and prevent enteroviral illness now!  Please talk to your MP as soon as possible about why similar studies are not being carried out within the UK despite large amounts of money being provided!! 


Polioencephalitis and the brain fatigue generator model of post-viral fatigue syndromes. Bruno RL, Frick NM, Creange S, Zimmerman JR, Lewis T. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 5-27.

Abstract: Fatigue is the most commonly reported and most debilitating Post-Polio Squelae (PPS), affecting millions of polio survivors world-wide. Post-polio fatigue is associated with: (1) subjective reports of difficulty with attention, cognition, word-finding and maintaining wakefulness; (2) clinically significant deficits on neuropsychological tests of information processing speed and attention; (3) gray and white matter hyperintensities in the reticular activating system on magnetic resonance imaging of the brain; (4) neuroendocrine evidence of impaired activation of the HPA axis. Many of these findings are identical to those documented following a variety of viral encephalitides, including acute poliovirus infection, lethargic encephalitis, Iceland Disease, myalgic encephalomyelitis, and, most recently, Chronic Fatigue Syndrome. The clinical, historic, neuropsychologic, neuroanatomic and physiologic parallels between poliovirus infection, post-polio fatigue and post-viral fatigue syndromes (PVFS) will be explored in an attempt to describe the pathophysiology of PVFS. The disinhibition of a putatitve Brain Fatigue Generator will be implicated as a cause of the subjective symptoms and objective signs that accompany PVFS. The results of a pilot placebo-controlled study of a dopamine 2 receptor agonist to treat post-polio fatigue will also be described.


Chronic fatigue, fainting and autonomic dysfunction: further similarities between post-polio fatigue and chronic fatigue syndrome? Bruno RL. Journal of Chronic Fatigue Syndrome 1997; 3(3): 109-116.

Abstract: To test the hypothesis that fatigue and fainting occur together, 1,047 polio survivors and 419 non-disabled control subjects were asked about the frequency and cause of fainting and asked to rate their typical daily fatigue severity. Fatigue severity was significantly higher in polio survivors as compared to controls, and in both polio survivors and controls who had fainted, as compared to those who had not. Daily fatigue severity also increased in both groups as the number of lifetime faints increased. Fatigue was significantly higher in controls who fainted one time and three times as compared to controls who had never fainted. Daily fatigue severity was significantly higher in polio survivors who had fainted three, four and five times as compared to those who had never fainted. These findings suggest a physiological relationship between fatigue and fainting, possibly attributable to the close proximity of cardiovascular regulation and brain activation centers within the brain stem. Fatigue and hypotension in patients with chronic fatigue syndrome and in polio survivors with late-onset fatigue may result from damage to brain stem and hypothalamic neurons.

General viral research

From ‘What is M.E.?(on this site):

Myalgic Encephalomyelitis is a debilitating acquired illness which has been recognised by the World Health Organisation (WHO) since 1969 as an organic neurological disorder. ME can occur in both epidemic and sporadic forms (over 60 outbreaks have been recorded worldwide since 1934) and appears to be remarkably similar to post-polio syndrome (an enteroviral triggered disorder). ME can be extremely severe and in some cases the illness is fatal.

Myalgic Encephalomyelitis is an acutely acquired neurological illness (with systemic effects) initiated by a virus infection. This point of view is supported by history (ME epidemics have followed polio epidemics and serological studies have shown that communities affected by an outbreak of M.E. were effectively blocked (or immune) from the effects of a subsequent polio outbreak), incidence (correlation with a flu-like prodromic illness), symptoms (swollen lymph nodes, low-grade fever, sore throat), and similarities with other viral ailments, notably mononucleosis and post-polio syndrome. Research also supports a viral causation for the illness.

There is a history of recorded outbreaks going back to 1934, when an epidemic of what seemed at first to be poliomyelitis was reported in Los Angeles. A review of early outbreaks found that clinical symptoms were consistent in over sixty recorded epidemics of M.E. spread all over the world.

Although the illness we now know as Myalgic Encephalomyelitis has existed for centuries, for much of that time it was a relatively uncommon disease. Following the mass polio vaccination programs of the 1960’s cases of polio were greatly reduced and outbreaks of M.E. seemed to be similarly affected. It wasn’t until the late 1970’s that M.E. began (for reasons as yet not fully understood) its dramatic increase in incidence worldwide. Over 20 years later, M.E. is a worldwide epidemic of devastating proportions. Many people have died from M.E. and there are now millions of people severely disabled by this epidemic.

Veteran M.E. specialist Dr Byron Hyde explains that: '[The] prodromal phase is associated with a usually short onset or triggering illness. This onset illness usually takes the form of either, or any combination, of the following, (a) an upper respiratory illness, (b) a gastrointestinal upset, (c) vertigo and (d) a moderate to severe meningitic type headache. These are only the most common onset illnesses or symptoms of which there are several. The onset illness is associated with either a low grade or subnormal temperature, headaches, sometimes persisting and accentuated by movement with intermittent attacks of vertigo or dizziness. Evidence of a previous immune insult [such as a recent immunisation] is found regularly in both epidemic and sporadic cases. The usual incubation period of the triggering illness is 4-6 days. The second and third phases of the illness are usually always different in nature from the onset illness and usually become apparent within 1-4 weeks.'

There appears to be somewhat of an occupational bias towards teachers (students) and health care workers in the incidence of Myalgic Encephalomyelitis cases (and outbreaks). These higher risk groups do not work in environments which are more stressful than the average job, but these are jobs which require higher rates of immunisation than others. This relationship with inoculation is often seen in infectious illnesses.

The main period of infectivity of M.E. peaks at the time just before symptoms appear through to the initial acute phase of the illness (which lasts for several months or in some cases years). M.E. appears to be highly infective but also highly selective. Modes of transmission are thought to include: casual contact (respiratory), salivary transmission (eg. kissing), sexual transmission and transmission through blood products. There is also evidence that asymptomatic carrier of the illness may be able to pass the illness on to others for a brief period following their exposure to the illness. (During the recovery and/or chronic stages of the illness however M.E. does not appear to present a significant infective risk).

The US Centres for Disease Control (CDC) placed 'CFS' on its "Priority One; New and Emerging" list of infectious diseases some years ago; a list that also includes Lyme disease, hepatitis C, and malaria.’ But it seems that is the only real ‘action’ they’ve taken. No real research into transmissibility (or more importantly on reducing infection rates) has been done by the Government despite ample evidence that this is an infectious disease. There have been many well-documented clusters or outbreaks of the illness, reports of 4.5% of people contracting the illness after blood transfusions (or after needle-stick injuries involving the blood of ME patients), evidence of the disease spreading through casual contact amongst family members and so on.

As Dr Elizabeth Dowsett explains: ‘The problem we face is that, in spite of overwhelming epidemiological and technical evidence of an infectious case, the truth is being suppressed by the government and the 'official' M.E. charities as 'too scary' for the general public.’

This pretence of ignorance on behalf of Government has had enormous consequences; only in the UK are people with ME directly banned from donating blood for example. So it is that the number of people infected with ME continues to rise unabated and largely unnoticed by the public.

M.E. is at least as common as Multiple Sclerosis. Children and teenagers are also susceptible to the illness and children as young as five have been diagnosed with M.E. One hundred thousand kids are estimated to have M.E. in the US alone and a recent study in the UK found that M.E. was by far the most common reason for a child’s long term absence from school. Women are affected around three times as often as men, a ratio common in autoimmune disorders (although in children the sexes seem to be afflicted equally). M.E. affects all races and socio-economic groups and has been diagnosed all over the world.

Transmission of M.E. to monkeys has been successfully demonstrated and has produced central nervous system and parasympathetic nervous system injury in at least two separate sets of experiments; in 1934 where ‘cross sections of the spinal cord demonstrated numerous minute haemorrhages in the grey matter’ and in 1949-51 in the Adelaide, Australia epidemic of M.E. where a radiculitis of the sciatic nerve was demonstrated with small punctate lesions of the myelin sheath (Hyde & Jain 1992, p. 40).

M.E. is an infectious neurological disease and represents a major attack on the central nervous system (CNS) by the chronic effects of a viral infection. A significant number of the world’s leading M.E. experts believe that M.E., like poliomyelitis, is caused by an enterovirus. (This includes doctors such as A. Gilliam, A. Melvin Ramsay and Elizabeth Dowsett, John Richardson of Newcastle-upon-Tyne, W.H. Lyle, Elizabeth Bell of Ruckhill Hospital, James Mowbray of St Mary’s, Peter Behan and also the brilliant Byron Hyde of Canada.) The evidence which exists to support this theory is compelling (Hyde 2007, [Online]) (Hyde 2006, [Online]).

Enterovirus infections are able to cause:

  1. a chronic host infection
  2. major or no cardiac disease depending on the virulence of the subtype
  3. cardiac injury dependent upon the sex of the patient and of the level of physical activity of the patient during the acute or infectious stage
  4. cardiac disease depending upon the immunological variability of the host (Hyde & Jain 1992a, p. 40).

An enterovirus would also explain the; age variation, sex variation, obvious resistance of some family members to the infection and the effect of physical activity (particularly in the early stages of the illness) in creating more long-term/severe M.E. illness in the host (Hyde & Jain 1992a, p. 40). There is also the evidence that; M.E. epidemics very often followed polio epidemics, M.E. resembles polio at onset, serological studies have shown that communities affected by an outbreak of M.E. were effectively blocked (or immune) from the effects of a subsequent polio outbreak, evidence of enteroviral infection has been found in the brain tissue of M.E. patients at autopsy, and so on (Hyde 2007, [Online]) (Hyde 2006, [Online]) (Hyde 2003, [Online]) (Dowsett 2001a, [Online]) (Dowsett 2000, [Online]) (Dowsett 1999a, 1999b, [Online]) (Hyde 1992 p. xi) (Hyde & Jain 1992 pp. 38 - 43) (Hyde et al. 1992, pp. 25-37) (Dowsett et al. 1990, pp. 285-291) (Ramsay 1986, [Online]) (Dowsett & Ramsay n.d., pp. 81-84) (Richardson n.d., pp. 85-92) (Richardson 1999, [Online]).

M.E. expert Dr Elizabeth Dowsett writes about Myalgic Encephalomyelitis that: ‘This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory’ (Dowsett et al. 1990, pp. 285-291).

See below for more information.


The Clinical and Scientific Basis of Myalgic Encephalomyelitis Edited by Byron Hyde, M.D. , Nightingale Research Foundation, Ottawa, Canada

‘It is a fact that the majority of M.E. patients are not in high-stress occupations as the popular press frequently suggests, but are teachers, nurses, physicians, and other health care workers. This group represents those most closely related to infectious illness, frequent immunisations and those most frequently immunised.’

‘Up to 1955, recognised M.E. was clearly previously associated with poliomyelitis. The viruses that cause paralytic poliomyelitis are some of the same viruses that cause M.E. But these enteroviruses that are capable of causing paralysis attach to more than one set of tissue receptors. These other receptors are found on different cells in the brain and spine as well as in other body areas. The symptoms described by M.E. sufferers are due to injury to these other cells.’

Note: This book contains an enormous amount of information on the epiemics of M.E. (and many other aspects of M.E.) that is simply not available anywhere else. Each epidemic is listed and many are gone into in great detail, information is given on transmissibility, onset and on the historical facts of each outbreak (for example; the links with Polio and how sufferers of one early outbreak were actually paid to keep silent about what had happened to them!). This book is essential reading for anyone with an interest in M.E.


The Nightingale Definition of Myalgic Encephalomyelitis (M.E.)  by Dr Byron Hyde 2006

'Under epidemic and primary M.E. there is no consensus as to the viral or infectious cause. Much of this lack of consensus may be due to the non-separation of acute onset from gradual onset patients in the M.E. and CFS groups of patients. Primary M.E. is always an acute onset illness.

Doctors A. Gilliam, A. Melvin Ramsay and Elizabeth Dowsett, John Richardson of Newcastle-upon-Tyne, W.H. Lyle, Elizabeth Bell of Ruckhill Hospital, James Mowbray of St Mary’s and Peter Behan all believed that the majority of primary M.E. patients fell ill following exposure to an enterovirus (Poliovirus, ECHO, Coxsackie and the numbered viruses are the significant viruses in this group).

I share this belief. Unfortunately, it is very difficult to recover polio and enteroviruses from live patients. Dr. James Mowbray developed a test that demonstrated enterovirus infection in many M.E. patients but I do not believe he qualified his patients by acute or gradual onset type of illness. In my tests in Ruckhill Hospital in Glasgow, I found confirmation of enteroviral infection only in acute onset patients and not in any gradual onset [ie. CFS] patients. Few physicians realize that almost all cases of poliovirus recovered from poliomyelitis victims came from cadavers. At the very least, these enteroviruses must be recovered from patients during their onset illness and this has rarely been done. An exception is in the case of the Newton-le-Willows Lancashire epidemic where Dr. W. H. Lyle’s investigation recovered ECHO enterovirus. Recent publications by Dr. J. R. Kerr have also identified the fact that enteroviruses are one of the most likely causes of M.E. If this belief is correct, many if not most of the M.E. illnesses could be vanquished by simply adding essential enteroviral genetic material from these enteroviruses to complement polio immunization.'

'It has become obvious to me that we are dealing with both a vasculitis and a change in vascular physiology. Numerous other physicians have supported this finding. Dr. David Bell, who rediscovered the work of Dr. David Streeten and his book, Orthostatic Disorders of the Circulation: Mechanisms, Manifestations and Treatment, New York: Plenum Medical, 1986, advanced this understanding of M.E. The work of Dr. Vance Spence and his colleagues in Scotland have started to nail this CNS-vascular relationship down even further with a series of major research papers. The recent interpretation of the cause of Multiple Sclerosis (MS) as an injury of the microvasculization causing the injury of the schwann cells that in turn causes the demyelination injuries of MS has been added to that of paralytic poliomyelitis as an essential vascular injury. Paralytic poliomyelitis was thought to be a primary injury to the anterior horn cells of the spinal cord but is now recognized as a vasculitis injuring the circulation to the anterior horn cells. Poliomyelitis is generally a non-progressive, specific site injury, although post-polio syndrome has challenged that belief. MS is a recurrent more fulminant physiological vascular injury.

M.E. appears to be in this same family of diseases as paralytic polio and MS. M.E. is definitely less fulminant than MS but more generalized. M.E. is less fulminant but more generalized than poliomyelitis. This relationship of M.E.-like illness to poliomyelitis is not new and is of course the reason that Alexander Gilliam, in his analysis of the Los Angeles County General Hospital M.E. epidemic in 1934, called M.E. atypical poliomyelitis.'

'M.E. is a clearly defined disease process. CFS by definition has always been a syndrome. At one of the meetings held to determine the 1994 U.S. Centers for Disease Control and Prevention (CDC) definition of CFS, in response to my question from the floor, Dr. Keiji Fukuda stated that numerous M.E. epidemics—he cited the Los Angeles County Hospital epidemic of 1934, the Akureyri outbreak of 1947-48 and the 1955-58 Royal Free Hospitals epidemics-- were definitely not CFS epidemics. Dr. Fukuda was correct.'

*HIGHLY RECOMMENDED*


Are Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Synonymous Terms? by Byron Hyde MD

Byron M. Hyde, M.D. Presented at 1998 International ME Conference, Sydney

A Record of Myalgic Encephalomyelitis Epidemics: A basic factor about ME throughout its history is that it does occur in epidemics. This fundamental aspect is essential. This fact conveys, among other things, the infectious and contagious nature of our disease. These characteristics of our disease are strictly avoided by the health agencies. It could be said that a strategic aspect of the health agency policies has been to conceal the history of ME.

An important chapter in the Encyclopaedia of Myalgic Encephalomyelitis contains a very fundamental disclosure of ME by documenting the outbreaks from 1934 to 1990. This chapter is the result of work carried out over many years by Drs. Acheson, Henderson, Shelokov and Parish. We are profoundly grateful to these doctors and their vigilance over the years to evaluate and keep track of these outbreaks.

"It is thus important that those that attempt to define any disease or illness to have long term clinical experience with patients with this illness. There is simply no place for the bureaucrat in defining illness. All definition of epidemic or infectious illness must be based upon persistent clinical examination of the afflicted patient, an understanding and exploration of the environmental factors producing that illness, and pathophysiological examination of tissue from those patients. For similar reasons, I believe that the inclusion of psychiatrists in the defining of an epidemic and obviously disease of infectious origin, simply muddies the water for any serious understanding of that disease. The UK definition of CFS was developed by a panel of physicians who were primarily psychiatrists, with few if any clinicians who had ever looked at an epidemic of CFS. A serious attempt must be made to look at epidemic disease as and where that disease starts. This has not been done by those who have defined CFS in the USA nor in the United Kingdom and this factor alone is probably the single greatest reason why we know so little about CFS today that we did not know in 1984."

Myalgic Encephalomyelitis (M.E.) This is a term used to describe an epidemic and sporadic disease process that is associated with a chronic debilitating illness of children and adults. Variants of this term M.E. were first used following a series of repeating epidemics starting in May 1955 in the Royal Free Hospital in London England. New outbreaks of this illness continued until 1958 in various London area hospitals. M.E. and these epidemics are well described by A. Melvin Ramsay in his book Myalgic Encephalomyelitis and Post-Viral Fatigue States.

Dr. A. Melvin Ramsay followed many of those who fell chronically ill during this 1955-1958 epidemic period for up to 34 years, until he died in 1989. This type of epidemic continuity proved to be quite characteristic of the M.E. epidemics that occurred in Akureyri in 1947-1949, in the Royal Free epidemics and in the North American epidemic period that extended from 1984 to 1988 (In 1983 in New Zealand where this pan-epidemic may have originated. All of these epidemics occurred in the late summer and autumn, decreasing in winter, with a new small peak of new female cases at Christmas in the Northern Hemisphere. The numbers of new cases would then rapidly fall off as the winter months progressed, only to reappear in the late summer again.

Monthly pattern of onset of new M.E. illness. This M.E. type of epidemic that was first observed and documented in detail in the summer of 1934, Los Angeles County General Hospital Epidemic by Dr. Alexander (Sandy) Gilliam, is not uncommon. Over 60 similar but often less known epidemics have been documented by Dr. J. Gordon Parish.

These epidemics have been associated with certain particular characteristics. Onset can be at any season but most frequently occurs in summer or autumn. There appears to be a high prevalence of epidemics or clusters in schools, hospitals and institutions involving hospital staff. The usual incubation period of the triggering illness is 4-6 days. The second and third phases of the illness are usually always different in nature from the onset illness and usually become apparent within 1-4 weeks.’


A New and Simple Definition of Myalgic Encephalomyelitis and a New Simple Definition of Chronic Fatigue Syndrome & A Brief History of Myalgic Encephalomyelitis & An Irreverent History of Chronic Fatigue Syndrome by Dr Byron Hyde MD 2006

[This paper discusses several of the epidemics]

‘Do not for one minute believe that CFS is simply another name for Myalgic Encephalomyelitis (M.E.). It is not. Though CFS is based upon a typical M.E. epidemic, in my opinion it has always been a confused and distorted view of reality. The invention of Chronic Fatigue Syndrome has to be one of the most curious cases of inventive American scientific imperialism that one could imagine. It is my opinion that the CDC 1988 definition of CFS describes a non-existing chimera based upon inexperienced individuals who lack any historical knowledge of this disease process. The CDC definition is not a disease process.’

M.E. is not caused by the HHV6 virus: 'This virus was not associated with CFS until after the 1990 period. HHV6 is the virus that causes the benign childhood illness, Roseola. By 1986 HHV6 was already known to have an incubation period of 9 days due to human experimentation when the actual virus was injected into several children. See (Gorbac, Second Edition, Infectious Diseases, page 1335). When acquired by random infection, the incubation period of HHV6 Roseola was more like 12 days. So once again anyone with access to a library or a computer would have soon dispelled any view that HHV6 was a cause of M.E. epidemics where the incubation was approximately 7 days or less.'

M.E. is not caused by the Epstein Barr virus (or mononucleosis/glandular fever): 'The Lake Tahoe epidemic that started in August 1984 also started amongst students. In this case the epidemic began in a high school girls' basketball team that was travelling in a bus to play various other teams. The epidemic spread rapidly with an incubation period of approximately a week. As in many of the other epidemics, it then spread to the general community. After the epidemic started it then involved three high schools, both students and teachers and ultimately spread to the community. For some reason it was considered to be an epidemic of infectious mononucleosis. This is an illness caused by a virus Epstein Barr Syndrome. Associating the Lake Tahoe epidemic with Epstein Barr Syndrome was frankly ridiculous and you will see why almost immediately. Anyone who realizes that infectious mononucleosis is caused by the herpes family virus, Epstein Barr Virus (EBV), and that the incubation period of this illness is approximately 40 days, should have realized that you simply cannot have a rapidly spreading viral epidemic with a virus with a latent period of 40 days. Neither Dr Straus nor Dr Holmes, senior government physicians, should have fallen into such a trap. They only had to go to the excellent CDC library to realize that rather than spending half a million dollars or so on a publication that they should have known would not have incriminated EBV. Yet this epidemic somehow spread the myth that this illness was caused by EBV. Today, as I write this short history of M.E. the vast majority of physicians and the public still associate Epstein Barr Virus with [M.E.]. Such is the perseverance of error.'

'The incubation period from time of contact with the infection until the appearance of the illness is approximately 4-7 days. In its epidemic form M.E. was most commonly seen in (a) Health Care Workers, (b) children and older students in residential schools, nurses residences and hospitals, (c) in military barracks where students or soldiers were housed in close proximity further supporting the belief in its infectious nature. Although M.E. was not caused by poliovirus in the Akureyri epidemic, infection with M.E. somehow protected the patients from the polio epidemic that swept though Iceland in the 1950s. Polioviruses represent three of approximately 100 different enteroviruses. This was the reason why many in the UK believed that some of these epidemics were probably caused by a less lethal non-polio form of enteroviruses such as ECHO, Coxsackie, the numbered and new enteroviruses.'

*HIGHLY RECOMMENDED*


The postviral fatigue syndrome - an analysis of the findings in 50 cases. Behan PO, et al. Journal of Infection 1985; 10: 211-22.

Abstract: The clinical, pathological, electrophysiological, immunological and virological abnormalities in 50 patients with the postviral fatigue syndrome are recorded. These findings confirm the organic nature of the disease. A metabolic disorder, caused by persistent virus infection and associated with defective immunoregulation, is suggested as the pathogenetic mechanism.


Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H. Proceedings of the National Academy of Sciences of the United States of America 1991; 88(7): 2922-6.

Abstract: Chronic fatigue immune dysfunction syndrome (CFIDS) is a recently recognized illness characterized by debilitating fatigue as well as immunological and neurological abnormalities [Straus, S.E. (1988) J. Inf. Dis. 157, 405-412]. Once thought to be caused by Epstein-Barr virus, it is now thought to have a different but unknown etiology. We evaluated 30 adult and pediatric CFIDS patients from six eastern states for the presence of human T-lymphotropic virus (HTLV) types I and II by Western immunoblotting, polymearse chain reaction, and in situ hybridization of blood samples. The majority of patients were positive for HTLV antibodies by Western blotting and for HTLV-II gag sequences by polymerase chain reaction and in situ hybridization. Twenty nonexposure healthy controls were negative in all assays. These data support an association between an HTLV-II-like virus and CFIDS.


Cytomegalovirus-related sequence in an atypical cytopathic virus repeatedly isolated from a patient with chronic fatigue syndrome. Martin WJ, Zeng LC, Ahmed K, Roy M. American Journal of Pathology 1994; 145(2): 440-51.

Abstract: An atypical virus, cytopathic for human and animal fibroblasts, was repeatedly cultured from a patient with chronic fatigue syndrome. Viral particles, suggestive of cytomegalovirus (CMV) were seen by electron microscopy. Infected cells did not, however, stain with antisera specific for CMV, herpes, simplex virus, or human herpes-virus-6. Polymerase chain reaction (PCR) assays for these viruses were also negative. Two distinct products of approximately 1.5 kilobase pairs were amplified from virally infected cells using the human T lymphotropic virus-II tax gene reactive primer, SK44, in low stringency PCR. Sequencing of one of the amplified products showed a region of highly significant partial homology with the UL34 gene of CMV. The sequence of the other PCR product did not correspond with CMV or any other virus. DNA was extracted from the material pelleted by ultracentrifugation of filtered culture supernatants. It migrated in agarose gels as a single band of approximately 20 kpb. The banded DNA was digested with EcoRI and cloned. A 2.2 kbp plasmid containing the CMV-related sequence identified within the PCR product was recovered. Sequencing of this plasmid extended the region of partial sequence homology with CMV to include a portion of the UL35 gene of CMV. Initial sequencing of additional plasmids has confirmed the partial relatedness to CMV. The data indicate a novel type of CMV-related "stealth" virus that is able to establish a clinically persistent human infection.


Biochemical and muscle studies in patients with acute onset post-viral fatigue syndrome. Preedy VR, Smith DG, Salisbury JR, Peters TJ. Journal of Clinical Pathology 1993; 46(8): 722-6.

Abstract: AIMS-To investigate in detail various biochemical and pathophysiological indices of muscle pathology in acute onset post-viral fatigue syndrome (PVFS). METHODS-Twenty three patients with PVFS (of mean duration 4.6 years) were subjected to needle biopsy for histomorphometry and total RNA contents. Plasma analysis included serology and creatine kinase activities. Indices of whole body mass were also measured-namely, whole body potassium content and plasma carnosinase activities. RESULTS-About 80% of the patients had serology indicative of persistent enteroviral infection as determined by VP1 antigen assay. Only about 10% of that same group of patients had serological indications of current enterovirus infection by IgM assay; a separate subset of 10% showed antibody changes suggestive of reactivation of Epstein-Barr virus. Quantitative morphometric analysis of skeletal muscle fibres indicated that the quadriceps muscle was normal or displayed only minor abnormalities in 22 patients. The Quetelet's Index (body mass index) and whole-body potassium values (index of lean body mass) were not affected in PVFS. The mean plasma carnosinase and creatinine kinase activities were also generally normal in these patients. The mean muscle RNA composition-mg RNA/mg DNA-was significantly reduced in acute onset PVFS by about 15%. The protein:DNA ratio was not significantly affected. CONCLUSIONS-Patients with acute onset PVFS, therefore, lose muscle protein synthetic potential, but not muscle bulk. Histopathology is consistent with these observations. These perturbations may contribute to the apparent feature of perceived muscle weakness associated with the persistent viral infection in the muscle themselves.


Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. Intervirology 1995; 38(5): 269-73.

Abstract: To test for an association between chronic fatigue syndrome (CFS) and infections with Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), antibodies to these viruses were tested in the serum from three groups of individuals: (1) 10 CFS patients with chronic fatigue beginning with a clinical pattern of acute infectious mononucleosis [IM; true chronic IM (CIM)]; (2) 10 CFS patients whose illness did not start with acute IM (non-CIM), and (3) healthy controls. High EBV antibody titers were demonstrated in most patients. Antibodies to ZEBRA, a product of the immediate early EBV gene BZLF1, were detected in the serum of CFS patients at a higher frequency than in healthy controls. Antibody titers to HHV-6 and HHV-7 were also higher in the patients with CFS than in the controls. These results are consistent with the view that CFS patients may have reactivations of EBV, HHV-6 and HHV-7.

Subscribe to the HFME newsletter!

To subscribe just click here

Live Support

Exciting book news!

Click here to purchase the first HFME book!


The book 'Caring For The M.E. Patient' by Jodi Bassett includes a Foreword by international M.E. expert Dr Byron Hyde.

He writes:

"There is so much false information that is picked up and disseminated it is near impossible to hold one’s head above the water and sift through this morass of misinformation. Any attempt to seek the truth is always a major difficulty. Somehow, Jodi Bassett and Hummingbird have managed to plow through this field of weeds."

"This is a book that deserves being read, not only by patients and physicians with an interest in M.E. but the bureaucrats in the USA Centers for Disease Control who have done so much damage to the understanding of M.E. I recommend her book to all and wish it every best success."

Paperback $18.95
Hardcover $22.95