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.

Exercise research

*O* MYALGIC ENCEPHALOMYELITIS : A Baffling Syndrome With a Tragic Aftermath. By A. Melvin Ramsay M.D., Hon Consultant Physician, Infectious Diseases Dept, Royal Free Hospital. [Published 1986]

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 and this was illustrated by the aforementioned three patients admitted to hospital in an unconscious state; all three recovered completely. 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.


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 vascular absnormalities seen in M.E., and explains how these can be tested for.]


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

‘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 vascular absnormalities seen in M.E.]


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 vascular absnormalities seen in M.E., and explains how these can be tested for.]


Brain problems in ME – is there a simple explanation? by Dr Elizabeth Dowsett

"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 exhaustion) have been reported in SPECT scans of patients with ME,(2) the vast majority of whom complain of difficulty with short-term memory."

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


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]"


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]).

We also have ample evidence from other doctors who have a significant involvement with M.E. patients (although for various reasons they cannot be considered M.E. experts, as such), indicating that M.E. patients have an abnormal and negative response to exertion. This includes the following:

1.  In April 2003, Arnold Peckerman MD from New Jersey reported findings to the annual meeting of the American Physiological Society that demonstrated via a sophisticated test that after exercise, the heart of those with M.E.* pumped less blood than it did at rest. Peckerman is on record as saying that it is a ‘progressive disease’ and that, ‘Basically we are talking about heart failure. A drop in [blood pumped by the heart] during exercise is not a typical response.’

This important research showed that, without exception, every disabled M.E. patient is in heart failure. The New Jersey team found evidence of the “Q” problem in M.E.  “Q” stands for cardiac output in litres per minute.  In M.E. patients, Q values correlated, with great precision, with the level of disability. Q was measured using impedance cardiography, a clinically validated and Government agency-recognised algorithm. (Impedance cardiography is not experimental.)

Normal people pump 7 litres of blood per minute through their heart, with very little variance, and when they stand up, that output drops to 5 litres per minute (a full 30% drop, but this is normal). Those two litres are rapidly pooled in the lower extremities and capacitance vessels.  Normal people do not sense the 30% drop in cardiac output when they stand up because their blood pressure either stays normal or rises when they stand up, the body will defend blood pressure beyond anything else in order to keep the pulse going. 

What the New Jersey team found in people with M.E. was astonishing – when these disabled patients stand up, they are on the edge of organ failure due to extremely low cardiac output as their Q drops to 3.7 litres per minute (a 50% drop from the normal of 7 litres per minute).

The disability level was exactly proportional to the severity of their Q defect, without exception and with scientific precision. In this Peckerman study, the data on the disabled M.E. patients reveals that even when they are lying down, their Q is only 5 litres per minute. The lower the Q, the more time the patient will spend lying down because lying down is the only time they come close to having sufficient cardiac output to survive (Peckerman et al. 2003, [Online]) (Hooper et al. 2007, [Online]) (Web M.D. 2009, [Online]).

 

2. Dr Cheney (following on from the Peckerman study) explained recently that because it takes more metabolic energy for the heart to relax and fill with blood than it does for it to squeeze and pump blood, the hearts of people with M.E. don’t fill with the proper amount of blood before they pump which is what causes the reduced cardiac output and many of the symptoms of M.E. and much of the disability of M.E. (The following summary of Cheney’s work (most of which was made public only in the form of recorded lectures) is taken from the Corporate Collusion paper by Professor Malcolm Hooper et al.)

Cheney comments that patients with M.E. suffer from cardiac problems since they cannot pump sufficient blood to the heart. He explains that the inability of very ill patients to stand up is the body protecting itself from cardiac stress and possible death. Cheney explains that if patients draw down their lifestyle to live within the means of the reduced cardiac output, then progression into congestive cardiac failure (CCF) is slowed down, but if things continue to progress, a point will be reached where there is no adequate cardiac output, and dyspnoea will develop, with ankle oedema and other signs of congestive cardiac failure. In order to stay relatively stable, it is essential for the patient not to create metabolic demand that the low cardiac output cannot match. Attempts to push beyond limits will cause injury or death.

Cheney also explains that M.E. patients have a high heart rate but a low cardiac output. In M.E. there is a cardiac dimension that is independent of (but not excluding) autonomic function or blood volume. A mismatch between metabolic demand and cardiac output, even very briefly, will kill.  If the cardiac output goes down, in order not to die, there is a rise in noradrenergic tone (also involving the adrenal glands) to bring the output back up. This is a serious problem, because when the adrenals are exhausted, there will be low cardiac output. There is no such thing as an M.E. patient who is NOT hypothyroid: this has nothing to do with thyroid failure, but everything to do with matching metabolic demand and cardiac output.

Half of patients exhibit atrial cavitation, and when these patients stood up, the filling volume collapsed. M.E. patients "squeeze the hell" out of their left ventricle, resulting in a "whopping" 70% increase in left ventricular wall motion thickness. The reason why patients are squeezing so hard is because they do not have enough energy to fill the chambers of the heart properly so they are trying to compensate by squeezing a lot harder (ie. the way patients are compensating for this loss of cardiac output is by squeezing the left ventricle much harder). There are significant consequences of this. One consequence is that M.E. patients become asynchronised (ie. the heart can be filling and ejecting at the same time). If out of synchrony, the ventricle cannot cope, so cardiac output is severely degraded.

Cheney posits that when faced with a low Q, the body sacrifices tissue perfusion in order to maintain blood pressure:  ie. microcirculation to the tissues of the body is sacrificed to maintain blood pressure so that the person does not die in the face of too low a cardiac output. This compensation is what is going on in the M.E. patient. Cheney states that it is important to note that the body does not sacrifice tissue perfusion equally across all organ systems:  instead, it prioritises the order of sacrifice and one can observe the progression of M.E. in a patient by noting this prioritisation.

Two organ systems in particular have a protective mechanism (the Renin Angiotensin System, or RAS) against restricted tissue perfusion: the lung and the kidneys.  These organs can sustain the greatest degree of Q problems because of this extra protection. Additionally, the heart and the brain also have this extra protection, even in the face of an extremely low Q. Therefore the lung, the brain, the kidneys and the heart are a bit more protected from a drop in Q than the liver, the gut, the muscles and the skin.

a. The first to be affected is the skin:  if the microcirculation of the skin is compromised, several problems can arise.  The body cannot thermoregulate anymore: the patient cannot stand heat or cold and if the core temperature rises, the patient will not be able to sleep and the immune system will be activated.  In order to regulate that problem, the body will kick in thyroid regulation which will down-regulate in order to keep the body temperature from going too high.  The patient then develops compensatory hypothyroidism, which means that now the patient will have trouble with feeling cold.  Also, the body will not be able to eliminate VOCs (volatile organic compounds), which are shed in the skin’s oil ducts, so VOCs build up in the body’s fat stores and the patient becomes progressively chemically poisoned by whatever is present in the environment.

b. The second effect:  the next microcirculation to be sacrificed is that to the muscles and the patient will have exercise intolerance.  If things get still worse, the patient begins to experience pain in the muscles. If the microcirculation to the joints becomes compromised, the patient starts to have arthralgia linked to this circulatory defect.

c. The next system to be compromised is the liver and gut.  One of the first things the patient may notice in this stage of disease progression is that there are fewer and fewer foods that can be tolerated, partly because microcirculation is necessary for proper digestion. Also the body will not secrete digestive juices so whatever food is tolerated will not be digested: if food cannot be digested, there will be peptides that are only partially digested and therefore are highly immune-reactive; they will leak out of the gut into the bloodstream, resulting in food allergies or sensitivities.  The body will be unable to detoxify the gut ecology, so the gut will begin to poison the patient, who will feel as if poisoned, with diarrhoea, constipation, flatulence and other gut problems. 

d. The fourth affected system is the brain:  Cheney posits that there is a devastating effect in the brain as a result of liver / gut dysfunction, which can quickly toxify the brain, resulting in disturbances of memory and of processing speed. Also, the hypothalamus begins to destabilise the patient from the autonomic nervous system perspective. In all probability, the brain and heart suffer simultaneous compromise, but patients usually notice the brain being affected much earlier than the heart – this is because heart muscle cells have the greatest mitochondrial content of any tissue in the body, so when the mitochondria are impaired, the heart muscle has the greatest reserve.  Even if the patient is sedentary with not too much demand on the heart, they can still think and make great demands on the brain, and energy is energy, whether it is being used physically or cognitively.

The fifth affected system is the heart:  Cheney posits that the effect of compromised microcirculation upon the heart has an “a” part and a “b” part:  part “a” is the manifestation of microcirculation impairment and part “b” is “the event horizon”.

Part “a”: manifestation of microcirculation impairment: the initial manifestation of microcirculatory impairment of the heart is arrhythmia with exercise intolerance: when the patient goes upstairs, more cardiac output is needed but the patient cannot sustain it. When there are even more severe microcirculatory problems, the patient starts to get chest pain as the myocardial cells die because they cannot get adequate oxygen.

Part “b”: the event horizon: (once this line is passed, there is no going back): Cheney’s view is that when the microcirculation defect within the heart itself begins to impact Q, a vicious circle begins – microcirculation impairment reduces the Q, which produces more microcirculation impairment, which produces even more Q problems, so down goes the patient into the next phase of cardiac failure, which involves the lungs.

The sixth affected system is the lung and kidney:  this leads to congestive heart failure and pulmonary oedema, then the kidney is affected (the kidney is the last to go because it has the RAS back-up system).  Combined with liver impairment, this stage is known as hepatorenal failure. A patient will know if s/he eventually loses the ability to compensate if, when they lie down, they are short of breath. Cheney’s view is that cardiac muscle has lost power because the mitochondria are dysfunctional (ie. there is an energy-production problem in the cells).

The red blood cells of patients with M.E. have been found to be deformed. When deformed, they cannot get through the capillary bed, causing pain. An indication of such deformity is a drop in the sedimentation rate (SED, or ESR) and Cheney (along with Dr Hyde and other M.E. experts) has observed that when measured in a laboratory, M.E. patients’ sedimentation rate is the lowest he has ever recorded, which confirms that M.E. patients have an induced haemoglobinopathy. Cheney has stated that the M.E. patients with the lowest sedimentation rate may have the greatest degree of pain. The more deformed the red blood cells, the more pain may be experienced.  Some M.E. patients have a problem similar to that of sickle cell anaemia in this regard, and sickle cell patients have unbelievable pain.  Cheney emphasises that it is bad enough when patients do not perfuse their muscles and joints (because of poor microcirculation) but it is even worse when red blood cells are so deformed that they can barely get through the capillaries or are blocked entirely. Cheney notes that in the Laboratory Textbook of Medicine, there are only three diseases that lower the sedimentation rate to that level: one is sickle cell anaemia (a genetic haemoglobinopathy); the second is M.E. (an acquired haemoglobinopathy) and the third is idiopathic cardiomyopathy. (The latter being one way in which the cardiac problems of M.E. are described.)

Cheney observes that in order to improve cardiac output, patients need to lie down, as this increases the cardiac output by 2 litres per minute.  He notes that some patients need to lie down all the time to augment their blood volume in order to survive (Cheney 2006, [video recording]) (Peckerman et al. 2003, [Online]) (Hooper et al. 2007, [Online]).

Findings which showed mitochondrial dysfunction similar to mitochondrial encephalomyopathy also led Dr Cheney to comment, ‘The most important thing about exercise is not to have [patients with ME] do aerobic exercise. I believe that even progressive aerobic exercise is counter-productive. If you have a defect in mitochondrial function and you push the mitochondria by exercise, you kill the DNA’ (Williams 2004, [Online]).

  • Note that Dr Cheney cannot be said to be a M.E. expert, although he does deal primarily with M.E. patients and his comments on cardiac insufficiency can (and do) only relate to genuine M.E. patients as this finding is unique to M.E. patients. Unfortunately Cheney uses the terms ‘CFS’ and ‘CFIDS’ to refer to M.E. patients and, worse, unfortunately mixes in some medical and political facts about ‘CFS’ and ‘CFS’ patients (patients with diseases other than M.E.) into his 20 years of M.E. research. Thus not all of his work relates 100% to M.E. unfortunately. See: Is Cheney talking about M.E. or 'CFS'? for more information.

  • Dr Peckerman, like Cheney, has been involved in the study of the abnormalities unique to M.E. Unfortunately however he has used the terminology and definitions of ‘CFS’ and has included a vast amount of ‘CFS’ propaganda in his work. Thus while Dr Peckerman has some legitimate knowledge of the M.E. disease process, he cannot be considered a M.E. expert. Note also that both of these doctors do not use anything like the most severely affected M.E. patients in their research.

As these comments clearly indicate, the adverse response to physical activity in M.E. patients is not ‘medically unexplained’ – research has found a number of sound medical reasons why M.E. sufferers are so physically disabled and limited, and unable to maintain an upright posture. These include; evidence of damage to the central nervous system (and autonomic and sympathetic nervous systems, causing a loss of normal internal homeostasis), damage to cardiac muscle (and many other cardiac and cardiovascular abnormalities including evidence of cardiac insufficiency), abnormalities and damage to muscle, immune system abnormalities, respiratory abnormalities and also a variety of abnormalities at a cellular level (eg. mitochondrial defects).

It is also worth noting that none of these abnormalities can be explained by so-called ‘deconditioning’ – the supposed reason for the recommendation of therapies such as GET.


RESEARCH BREAKTHROUGH: ME/CFS AN INFECTIOUS CARDIOMYOPATHY? by: Philipa D. Corning, Ph.D., B.Sc. (Reviewed and approved by Dr. A. Martin Lerner)

In this study, 100% of the ME/CFS participants showed abnormal oscillating T-waves at 24 hr. holter monitoring and 24% showed weakened function on the left side of the heart (abnormal cardiac dynamics). This is the side of the heart that pumps oxygenated blood to all of the body, except the lungs. Data, gathered from biopsies and a 24-hour electrocardiogram (EKG) Holter monitor, showed that patients exhibited evidence of cardiomyopathy or disease of muscle in the heart.

These researchers tracked EKGs over a 24-hour period with a Holter monitor device and documented abnormal T-waves. This wave measures electrical recovery after contraction of the left ventricle. A normal T-wave should be shaped like the rolling crest of a wave in water. In 100% of ME/CFS patients, Lerner and his associates documented T-wave Inversions and/or T-wave flattenings. This finding is so consistent, they suggest that the Holter results should be included as part of the CDC case definition; it distinguishes ME/CFS patients from those with fatigue or unexplained origin. This research holds the potential to distinguish ME/CFS patients from FM patients, from those with other pain syndromes who do not relapse with exertion, and from those with fatigue associated with depression, which is a group that also does not suffer relapse with exertion. This work offers hard evidence to back up ME/CFS patients' much disbelieved claim that exercise is harmful and causes disease progression in ME/CFS.

In Dr. Lerner's model, the weakened heart is aggravated by physical activity, accounting for the post-exertional sickness and accounting for the post-exertional sickness so common in this disease - including flu symptoms, chills, fevers and increasing weakness. Indeed, the cardiac connection is what is so ground-breaking about this research.

In experiments with mice, Dr. Lerner has shown that raised myocardial coxsackie viral titers accompany physical exertion in the mice. When the heart muscle tissue is infected, overactivity causes death of cardiac tissue and disease progression. This is in direct conflict with the U.S. government research conclusions that ME/CFS disease symptoms are caused by underactivity due to a sedentary lifestyle. Dr. Lerner advises resting the heart in order to "do no harm" and to prevent death of cardiac tissue.

Dr. Lerner and associates also have documented abnormal ejection fractions in ME/CFS. Normally, over half of the blood in the left ventricle is ejected when the left ventricle contracts (part of the heart that pumps oxygenated blood out to the body). In Dr. Lerner's ME/CFS subjects, the ejection fraction is sometimes decreased, an indication that not all the normally-expelled blood leaves the ventricle. Some patients had reduced ejection fractions at rest while others had an ejection fraction that decreased during exercise from 51% to 36%. In a normal subject, the ejection fraction will rise over 5% during exercise. Stationary or falling ejection fraction is abnormal in coronary artery disease or cardiac muscle disease. Declining ejection fractions are not seen in normal persons leading sedentary lives.

These cardiac abnormalities are hypothesized to be virally induced.

This model explains the John Hopkins' finding of Rowe et al in which ME/CFS patients exhibited abnormal response to upright tilt. Lerner argues that it is abnormal cardiac response of cardiomyopathy instead of abnormal neural response. Indeed, Dr. Lerner's thesis explains a myriad of phenomenon that other research has not. For example, it explains why patients relapse with exertion and why only physically active young persons may acquire the disease. It also explains why stress is a major aggravator in this disorder. Stress may aggravate both herpes viruses and heart conditions. It also explains the anti-viral lymphocyte enzyme system, the 2-5 A pathway, suggesting the presence of a chronic infection.

In short, Dr. Lerner's work explains why previously healthy, vigorous young adults fall ill with chronic cardiomyopathy due to viral infection and cannot exercise for fear of causing further heart damage. This is directly opposite to the work of Dr. Stephen Straus at National Institute of Health (NIH) whose theory states that ME/CFS is a psychiatric disorder. This new research of Dr. Lerner et al is both refreshing and insightful. Needless to say, it has also been long awaited.


*O* Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome.
La Manca JJ; Sisto SA; De Luca J; Johnson SK; Lange G; Pareja J; Cook S; Natelson BH  C.F.S. Cooperative Research Center, University of Medicine and Dentistry of New Jersey- New Jersey Medical School, Newark, USA.Am J Med 1998 Sep 28; 105(3A):59S-65S (ISSN: 0002-9343)

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.


 "Subclassifying Chronic Fatigue Syndrome through Exercise Testing." Vanness JM, Snell CR, Strayer DR, Dempsey L 4th, Stevens SR.Med Sci Sports Exerc. 2003 Jun;35(6):908-913. [PDF Format]


Response to Exercise

Healthy People

ME/CFS Patients

Sense of well-being

Invigorating, anti-depressant effect

Malaise, fatigue, worsening of symptoms.

Resting heart rate

Normal

Elevated

Heart rate at maximum workload

Elevated

Reduced heart rate

Maximum oxygen uptake

Elevated

Approximately ½ of sedentary controls

Age-predicted target heart rate

Can achieve it

Can NOT achieve it

Heart functioning

Increased

Sub-optimal

Cerebral blood flow

Increased

Decreased

Body temperature

Increased

Decreased

Respiration

Increased

Decreased

Cognitive processing

Normal, more alert

Impaired

Oxygen delivery to the muscles

Increased

Reduced

Gait Kinematics

Normal

Abnormalities

Recovery period

Short

Days or weeks

*O* ME/CFS Post-Exertional Malaise / Fatigue and Exercise by Marjorie van de Sande B.Ed, Grad. Dip. Ed.

An excerpt:

Even though post-exertional malaise is a hallmark feature of ME/CFS, exercise programs are often prescribed with little thought to the effect they may have on patients. The panel of experts for the ME/CFS clinical consensus document(1) stressed that a thorough evaluation of patients and their total illness burden, optimizing medical management, and a careful evaluation of pain generators and risk factors must be done before even considering an exercise program. As much care must be taken in prescribing appropriate exercise for ME/CFS patients as in prescribing pharmaceuticals.(5)

[Note that recovery may be incomplete in some patients even after 'days or weeks' as this chart states. Symptom execerbation or progression may in fact persist for many months or years following exertion, or may be irreversible. This website also does not support use of the inadequate term 'fatigue' to describe the symptomatology of ME]


*O* Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects. Whistler T, Jones JF, Unger ER, Vernon SD.Journal: BMC Physiol. 2005 Mar 24;5(1):5  PMID: 15790422

BACKGROUND: Chronic fatigue syndrome (CFS) is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge. METHODS: Women with CFS and healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum
workload. Blood was obtained before and after the challenge, total RNA was extracted from mononuclear cells, and signal intensity of the labeled cDNA
hybridized to a 3800-gene oligonucleotide microarray was measured. We identified differences in gene expression among and between subject groups before and after exercise challenge, and evaluated differences in terms of Gene Ontology categories. RESULTS: Exercise-responsive genes differed between CFS cases and controls. These were in genes classified in chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport, and G protein-coupled receptor ontologies. Differences in ion transport activity/ion channel activity were evident at baseline and were exaggerated after exercise as evidenced by greater numbers of differentially genes in these molecular functions.

CONCLUSIONS: These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.

[Note: This is an Open Access article.  The complete article is available for free in PDF format at
http://www.biomedcentral.com/content/pdf/1472-6793-5-5.pdf .]


Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome. Sisto SA, Tapp W, Drastal S, Bergen M, DeMasi I, Cordero D, Natelson B. Clinical Autonomic Research 1995; 5(3): 139-43.

Abstract: Patients with chronic fatigue syndrome (CFS) often complain of an inability to maintain activity levels and a variety of autonomic-like symptoms that make everyday activity intolerable at times. The purpose of the study was to determine if there were differences in vagal activity at fixed breathing rates in women with CFS. Twelve women with the diagnosis of CFS between the ages of 32 and 59 years volunteered for the study. Healthy women, who were between the ages of 30 and 49, served as controls. Full signal electrocardiograph and respiratory signals were collected during a paced breathing protocol of three fixed breathing rates (8, 12 and 18 breaths/min) performed in the sitting and standing postures. Vagal activity was analyzed by means of heart rate spectral analysis to determine the subject's response to specific breathing rates and postures. Heart rate variability was used as a non-invasive method of measuring the parasympathetic component of the autonomic nervous system. Using this method, although there was significantly less vagal power in the sitting versus the standing postures for both groups, the overall vagal power was significantly lower (p < 0.034) in the CFS group versus healthy controls. Vagal power was also significantly lower (p < 0.01 to p < 0.05) at all breathing rates in both postures except while standing and breathing at 18 breaths/min. Knowledge of the differences in vagal activity for CFS patients may allow stratification for the analysis of other research variables.


*O* From the Assistant Secretary of Health Dr Philip Lee, U.S. Chair of Chronic Fatigue Syndrome Co-ordinating Committee (CFSCC), 13 September 1996:

There is mounting evidence that:

  a.. early diagnosis and aggressive rest, particularly in the initial stage, can have a crucial influence on duration, severity and recovery;
  b.. each person with ME/CFS (child or adult) has to find his/her own safe limits and can not have activity, mental or physical, prescribed by others;
mental activity can be every bit as detrimental as physical exertion.


 
A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome. Yamamoto Y, LaManca JJ, Natelson BH. Department of Neurosciences, New Jersey Medical School, East Orange, New Jersey 07018-1095, USA.

The use of symptoms generated by head up tilt (HUT) is not a useful tool in identifying chronic fatigue syndrome (CFS). We investigated whether heart rate variability (HRV) assessed early during HUT might be useful. A sample of 46 female subjects (24 with CFS and 22 sedentary, age-matched healthy controls; CON) who had exhibited no difference in time to syncope during tilt was examined for HRV responses to 10 min of 70 degrees HUT after 5 min of baseline in the supine position. HRV data were analyzed by the method of coarse graining spectral analysis. Variables compared between groups included mean and standard deviation (SD(RRI)) of RR intervals (RRI), amplitudes of low- (A(LF); 0.04-0.15 Hz) and high-frequency (A(HF); >0.15 Hz) harmonic as well as aperiodic, fractal (A(FR); 1/f(beta)) spectral components, the spectral exponent beta, and the difference in these values between baseline and HUT for each subject. In the supine baseline, only mean RRI was significantly (P < 0.01) lower in CFS than in CON. During HUT, however, mean RRI (P < 0.01), SD(RRI) (P < 0.01), A(HF) (P < 0.05), and A(FR) (P < 0.01) were significantly lower in CFS than in CON. When the difference in values between baseline and HUT for each subject was examined, only the difference for A(FR) (deltaA(FR)) was significantly (P < 0.01) lower in CFS than in CON, suggesting that A(FR)is a disease-specific response of HRV to HUT. When a cut-off level was set to deltaA(FR) = -2.7 msec, the sensitivity and the specificity in differentiating CFS from controls were 90% and 72%, respectively. The data suggest that a decrease in aperiodic fractal component of HRV in response to HUT can be used to differentiate patients with CFS from CON.
 

 
*O**O* Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Department of Human Physiology, Faculty of Physical Education and Physical Therapy Science, Vrije Universiteit Brussel, Brussel 1090, Belgium. jo.nijs@vub.ac.be

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.
 

 
Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Blackwood SK, MacHale SM, Power MJ, Goodwin GM, Lawrie SM. Edinburgh University Department of Psychiatry, Royal Edinburgh Hospital, UK.

OBJECTIVES: Patients with chronic fatigue syndrome complain of physical and mental fatigue that is worsened by exertion. It was predicted that the cognitive and motor responses to vigorous exercise in patients with chronic fatigue syndrome would differ from those in depressed and healthy controls. METHODS: Ten patients with chronic fatigue syndrome, 10 with depressive illness, and 10 healthy controls completed cognitive and muscle strength testing before and after a treadmill exercise test. Measures of cardiovascular functioning and perceived effort, fatigue, and mood were taken during each stage of testing. RESULTS: Depressed patients performed worst on cognitive tests at baseline. During the treadmill test, patients with chronic fatigue syndrome had higher ratings of perceived effort and fatigue than both control groups, whereas patients with depression reported lower mood. After exertion, patients with chronic fatigue syndrome showed a greater decrease than healthy controls on everyday tests of focused (p=0.02) and sustained (p=0.001) attention, as well as greater deterioration than depressed patients on the focused attention task (p=0.03). No between group differences were found in cardiovascular or symptom measures taken during the cognitive testing. CONCLUSIONS: Patients with chronic fatigue syndrome show a specific sensitivity to the effects of exertion on effortful cognitive functioning. This occurs despite subjective and objective evidence of effort allocation in chronic fatigue syndrome, suggesting that patients have reduced working memory capacity, or a greater demand to monitor cognitive processes, or both. Further insight into the pathophysiology of the core complaints in chronic fatigue syndrome is likely to be realised by studying the effects of exercise on other aspects of everyday functioning.
 

 
*O* Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Stewart JM. Department of Pediatrics, The Center for Pediatric Hypotension, New York Medical College, Valhalla 10595, USA.

The objective was to determine the nature of autonomic and vasomotor changes in adolescent patients with orthostatic tachycardia associated with the chronic fatigue syndrome (CFS) and the postural orthostatic tachycardia syndrome (POTS). Continuous electrocardiography and arterial tonometry was used to investigate the heart rate and blood pressure responses before and 3-5 min after head-up tilt in 22 adolescents with POTS and 14 adolescents with CFS, compared with control subjects comprising 10 healthy adolescents and 20 patients with simple faint. Heart rate and blood pressure variability, determined baroreceptor function using transfer function analysis, and measured cardiac vagal and adrenergic autonomic responses were calculated using timed breathing and the quantitative Valsalva maneuver. Two of 10 healthy controls and 14 of 20 simple faint patients experienced vasovagal syncope during head-up tilt. By design, all CFS and POTS patients experienced orthostatic tachycardia, often associated with hypotension. R-R interval and heart rate variability were decreased in CFS and POTS patients compared with control subjects and remained decreased with head-up tilt. Low-frequency (0.05-0.15 Hz) blood pressure variability reflecting vasomotion was increased in CFS and POTS patients compared with control subjects and increased further with head-up tilt. This was associated with depressed baroreflex transfer indicating baroreceptor attenuation through defective vagal efferent response. Only the sympathetic response remained. Heart rate variability declined progressively from normal healthy control subjects through syncope to POTS to CFS patients. Timed breathing and Valsalva maneuver were most often normal in CFS and POTS patients, although abnormalities in select individuals were found. Heart rate and blood pressure regulation in POTS and CFS patients are similar and indicate attenuated efferent vagal baroreflex associated with increased vasomotor tone. Loss of beat-to-beat heart rate control may contribute to a destabilized blood pressure resulting in orthostatic intolerance. The dysautonomia of orthostatic intolerance in POTS and in chronic fatigue [syndrome] are similar.
 

Increased Resting Energy Expenditure in the Chronic Fatigue Syndrome Walter S. Watson, PhD Donald C. McMillan, PhD Abhijit Chaudhuri, DM, MD Peter O. Behan, MD, DSc Journal of Chronic Fatigue Syndrome Vol.4 (4) 1998

It has been suggested that resting energy expenditure may be raised in chronic fatigue syndrome due to an upregulation of transmembrane ion transport. We measured resting energy expenditure by indirect calorimetry in 11 women with chronic fatigue [syndrome] and in 11 healthy women. Total body potassium, by whole body counting, and total body water, extracellular water and intracellular water, by a bioelectrical impedance method, were also measured.

When individual resting energy expenditure was predicted on the basis of total body potassium values for the chronic fatigue [syndrome] group, 5 out of 11 of these subjects had resting energy expenditure above the upper limit of normal as defined by the control group data. This is consistent with the hypothesis that there is upregulation of the sodium-potassium pump in chronic fatigue syndrome.


*O* Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue [syndrome] . Am J Physiol Heart Circ Physiol 2002 Jan;282(1):H66-H71 William B. Farquhar [1,2], Brian E. Hunt [2], J. Andrew Taylor [2], Stephen E. Darling [1], and Roy Freeman [1] [1] Center for Autonomic and Peripheral Nerve Disorders, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215; and [2] Laboratory for Cardiovascular Research, Hebrew Rehabilitation Center for Aged, Research and Training Institute, Harvard Medical School Division on Aging, Boston, Massachussetts 02131 NLM Citation: PMID: 11748048

Individuals with chronic fatigue syndrome (CFS) experience a number of somatic complaints including severe, disabling fatigue, and exercise intolerance. We hypothesized that hypovolemia, through its interaction with central hemodynamics, would contribute to the exercise intolerance associated with this disorder. We examined blood volume, peak aerobic power, habitual physical activity, fatigue level, and their interrelations to understand the physiological basis of this disorder. Seventeen patients who met the Centers for Disease Control criteria for CFS and 17 age-matched controls participated in the study. Blood volume was assessed using a single bolus injection of Evans blue dye. Peak oxygen consumption was measured during exercise on an upright cycle ergometer. Supine cardiac output and stroke volumes were measured using CO(2) rebreathing. Questionnaires were used to assess habitual physical activity and fatigue. Patients displayed a trend for a 9% lower blood volume (58.3 +/- 2.1 vs. 64.2 +/- 2.5 ml/kg, P = 0.084) and had a 35% lower peak oxygen consumption (22.0 +/- 1.2 vs. 33.6 +/- 1.9 ml/kg, P < 0.001). These two variables were highly related within the patients (r = 0.835, P < 0.001) and the controls (r = 0.850, P < 0.001). Peak ventilation and habitual physical activity were significantly lower in the patients. Fatigue level was not related to any of the measured physiological parameters within the CFS group. In conclusion, individuals with CFS have a significantly lower peak oxygen consumption and an insignificant trend toward lower blood volume compared with controls. These variables were highly related in both subject groups, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS.

[Note that the 'insignificant' trend toward lower blood volume of 9% was found in mild to possibly moderately ill patients. Very much higher percentages have been found in the more severely ill]


*O*
 
Circulating Blood Volume in Chronic Fatigue Syndrome
David H. P. Streeten, MB, DPhil, FRCP, FACP David S. Be11, MD, FAAP

ABSTRACT. Chronic fatigue syndrome (CFS) is an illness associated with severe activity limitation and a characteristic pattern of symptoms despite a relatively normal physical examination and routine laboratory evaluation. The recent description of delayed orthostatic hypotension in patients with CFS, and previous findings of reduced red blood cell (RBC) mass in other patients with orthostatic hypotension not known to have CFS, led us to measure RBC mass and plasma volume in 19 individuals (15 female, four male) with well characterized, severe CFS. RBC mass was found to be significantly reduced (p < 0.001) below the published normal range in the 16 women, being subnormal in 15 (93.8%) of them as well as in two of the four men. Plasma volume was subnormal in 10 (52.6%) patients and total blood volume was below normal in 12 (63.2%). The high prevalence and frequent severity of the low RBC mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients.

Conclusion: Of the 19 patients reported here, abnormalities in blood volume were very common. The most common, found in 16 of 19 patients, was a reduction in red blood cell mass. Eleven subjects had low plasma volumes, and total circulating blood volume was subnormal in 12 of 19 subjects. In some individuals this abnormality was strikingly severe. Patient #15, for example, had an RBC mass of 12.9 mL/Kg, which is 46% of the expected normal, and a total blood volume of 35.8 mL/Kg, which represents 49.7% of the expected normal value (21). Her peripheral hematocrit was not impressively low at 33.8%, presumably because of the symmetrical reduction in both RBC mass and plasma volume. In other patients the plasma volume was normal or even elevated in the face of a low RBC mass, and in nqne of these patients was the RBC mass abnormality detected by conventional interpretation of the peripheral hematocrit.

All of the subjects in this study had symptoms of orthostatic intolerance which probably contributed to their activity restriction, but tilt table and autonomic nervous system testing was not carried out systematically in these individuals. Normal sitting blood pressures were recorded in all patients under office visit circumstances, except for relatively low values in three and a mildly elevated blood pressure in one. Some of these patients have been tested subsequently and found to have delayed orthostatic hypotension (12), which may be characteristic for CFS (11,12). In general, blood pressure measurements were not predictive of the results of circulating blood volume measurements.


*O* Exercise Capacity in Chronic Fatigue Syndrome Pascale De Becker, PhD; Johan Roeykens, PT; Masha Reynders, PT; Neil McGregor, MD, PhD; Archives of Internal Medicine Vol. 160 No. 21, November 27, 2000 Kenny De Meirleir, MD, PhD

Background Patients with chronic fatigue syndrome (CFS) suffer from various symptoms, including debilitating fatigue, muscle pain, and muscle weakness. Patients with CFS can experience marked functional impairment. In this study, we evaluated the exercise capacity in a large cohort of female patients with CFS. Methods Patients with CFS and matched sedentary control subjects performed a maximal test with graded increase on a bicycle ergometer. Gas exchange ratio was continuously measured. In a second stage, we examined only those persons who achieved a maximal effort as defined by 2 end points: a respiratory quotient of at least 1.0 and an age-predicted target heart rate of at least 85%. Data were assessed using univariate and multivariate statistical methods. Results The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects. The maximal workload and maximal oxygen uptake attained by the patients with CFS were almost half those achieved by the control subjects. Analyzing only those persons who performed a maximal exercise test, similar findings were observed. Conclusions When compared with healthy sedentary women, female patients with CFS show a significantly decreased exercise capacity. This could affect their physical abilities to a moderate or severe extent. Reaching the age-predicted target heart rate seemed to be a limiting factor of the patients with CFS in achieving maximal effort, which could be due to autonomic disturbances.

Read the entire article here.

Excerpt:

This study clearly shows that patients with CFS are limited in their physical capacities. Based on the American Medical Association Guidelines for Impairment Rating,51 our 55.2% of patients who had a VO2max of less than 20 mL/kg per minute correspond to class 3-4 on the disability scale, indicating moderate to severe impairment.51 Regardless of the cause and pathogenesis, the symptom complex labeled CFS can and does result in prolonged debilitation.3, 4, 51

To our knowledge, this is the first study on exercise capacity in a large population of patients with CFS and sedentary control subjects. Physical capacity based on exercise tolerance is only one of a number of factors that might be considered in establishing a more global impairment rating. However, we believe it is a strong and useful tool in assessing a person's physical capability.


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 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.


09-08-2004 In Dr. Lapp's words:

This Cochrane review study is a sore subject! I obtained a copy of the entire review, and it is just horrible. The author examined 9 studies, accepted only 5, and none were from the USA. Here are some of the problems: 1. Fatigue was the main outcome measured; depression and quality of life were secondary outcome measurements. 2. Fukuda international criteria for Chronic Fatigue Syndrome (CFS) were used in only two studies, and it appears that the subjects were not terribly ill. 3. In two of the studies (Fulcher and Appleby), 80-92% of subjects were working at the time of the study; in Powell's study 35% were working. The others did not report. Obviously this was not a very sick cohort. 4. Of the 5 studies, the Appleby study was the only one with a rigorous exercise plan (70-75% of aerobic capacity for 30 minutes). This study did NOT show any improvement in subjects, and had the highest dropout rate. The 4 other studies used a low level of exercise (40% of aerobic capacity). 5. The so-called "experts' [plural] that were listed were Dr. Peter White [only], whom I believe works closely with Wessley and Sharpe. Read biased. 6. Even though the authors concluded "patients with CFS who are similar to those in the trials should be offered exercise therapy," the press did not make it clear that these CFS patients were rather high functioning, and that most CFS patients could not tolerate such exercise. 7. The authors also concluded from this same cohort that "exercise therapy may not worsen outcomes on average." This is very misleading since it is part of the Fukuda definition that exercise causes post-exertional malaise, and all Persons with Chronic Fatigue Syndrome (PWCs) may trigger prolonged relapses if they overexert. Sadly, this Cochrane review study once again sends the incorrect message to primary physicians -- that they should exercise all PWCs and not worry about post-exertional sequelae.

Charles W. Lapp, M.D. HUNTER-HOPKINS CENTER, P.A. specializing in CFS, ME, FM, and related illnesses.


Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome. Physiol Behav 2002 Sep;77(1):39 Ohashi K, Yamamoto Y, Natelson B. Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan NLM Citation: PMID: 12213500 Date sent: Sat, 7 Sep 2002

Post-exertional exacerbation of symptoms is one of the major characteristics of chronic fatigue syndrome (CFS). In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon. We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates. The peak value of autocorrelation coefficient (R) and the time between peak R's (circadian period, CP) were calculated. CFS patients had a lengthening (P<.05) of mean circadian period (MCP) that was longer than 24 h (P<.05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject's MCP (circadian period variability, CPV) before and after exercise for both groups. We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.


Respiratory symptoms and lung function testing in Chronic Fatigue Syndrome (CFS) patients P. De Becker, I. Campine, E. Van Steenberge, M. Noppen, A. Leysl, K. De Meirleir

Objective: The purpose of this study is to report the prevalence of respiratory symptoms in a cohort of CFS patients and to assess the usefulness and importance of pulmonary function testing in the clinical management of these patients. Methods: A sample of 55 consecutive CFS patients, who met the CDC (1988) and Fukuda (1994) criteria, were recruited from a university-based fatigue clinic in Brussels, Belgium. The following respiratory symptoms were observed in 46 of these patients (9 CFS patients did not present any respiratory symptoms at all): cough (19/55), medical history of allergy (8/55), new onset of allergy (16/55), chest tightness (6/55) and the major respiratory complaint appeared to be a pronounced exercise induced dyspnea (39/55).

A control group consisted of a community based sample of 39 age-and sex-matched individuals, not seeking medical care, and specifically denying any CFS related symptoms. Furthermore, they did not present any respiratory symptoms. Only 10 subjects showed a medical history of allergy (2 penicillin, 8 hayfever/house dust).
All patients and controls underwent a standardized pulmonary function testing, measuring following parameters: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), functional residual capacity (FRC), residual volume (RV), vital capacity (VC) and total lung capacity (TLC).

In all CFS patients, a histamine broncho-provocation test was additionally performed to determine the presence of bronchial hyper-responsiveness (defined as PD20 his < 2 mg histamine).

Statistical analysis was performed using descriptive statistics and a nonparametric Mann-Whitney test. Results: Compared to controls (A), CFS patients (B) do not show a significant difference in TLC (mean ± SD, A: 5.94 L ± 1.04 L; B: 5.72 L ± 1.005; p = 0.37). However, we found a significant difference between both groups in VC (A: 4.74 L ± 0.90 L; B: 4.255 ± 0.849; p < 0.01) and in RV (A: 1.19 L ± 0.33 L; B :1.479 ± 0.494; p < 0.01). In 33/55 (60%) patients a marked bronchial hyper-responsiveness was present. Conclusion: CFS patients show a significant decrease in VC, possibly due to a significant increase of RV. The incidence of bronchial hyper-responsiveness in this group is also remarkably high. These observations can, at least partially, explain the respiratory symptoms in these patients.


Lung function test findings in patients with chronic fatigue syndrome (CFS). F De Lorenzo, J Hargreaves, W Kakkar. Aust NZ J Med 1996:26:563-4


Motor cortex excitability in chronic fatigue syndrome.Starr A, Scalise A, Gordon R, Michalewski HJ, Caramia MD Clin Neurophysiol 2000 Nov 1;111(11):2025-2031 Department of Neurology, University of California, CA 92697-4290, Irvine, USA PMID: 11068238

Abstract
Objective:
To use transcranial magnetic stimulation (TMS) to definene motor cortical excitability in chronic fatigue syndrome (CFS) subjects during a repetitive, bilateral finger movement task. Methods: A total of 14 CFS patients were tested and compared with 14 age-matched healthy control subjects. TMS of the motor cortex (5% above threshold) was used to elicit motor evoked potentials (MEPs). Subjects performed regular (3-4/s) repetitive bilateral opening-closing movements of the index finger onto the thumb. MEPs of the first dorsal interosseus (FDI) were measured before, immediately following exercise periods of 30, 60 and 90 s, and after 15 min of rest. Results: Performance, defined by rate of movement, was significantly slower in CFS subjects (3.5/s) than in controls (4.0/s) independent of the hand measured. The rate, however, was not significantly affected by the exercise duration for either group. The threshold of TMS to evoke MEPs from the FDI muscle was significantly higher in CFS than in control subjects, independent of the hemisphere tested. A transient post-exercise facilitation of MEP amplitudes immediately after the exercise periods was present in controls independent of the hemisphere tested, but was absent in CFS subjects. A delayed facilitation of MEPs after 15-30 min of rest was restricted to the non-dominant hemisphere in controls; delayed facilitation was absent in CFS subjects.

Conclusions: Individuals with CFS do not show the normal fluctuations of motor cortical excitability that accompany and follow non-fatiguing repetitive bimanual finger movements.


Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Inbar O, Dlin R, Rotstein A, Whipp BJ.  Med Sci Sports Exerc 2001 Sep;33(9):1463-1470 Department of Life Sciences, Zinman College, Wingate Institute, ISRAEL; Links Clinic, Edmonton, CANADA; and Department of Physiology, St. George's Hospital Medical School, London, UNITED KINGDOM.

PURPOSE: The purpose of this investigation was to characterize the physiological response profiles of patients with chronic fatigue syndrome (CFS), to an incremental exercise test, performed to the limit of tolerance.

METHODS: Fifteen patients (12 women and three men) who fulfilled the case definition for chronic fatigue syndrome, and 15 healthy, sedentary, age- and sex-matched controls, performed an incremental progressive all-out treadmill test (cardiopulmonary exercise test).

RESULTS: As a group, the CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group. At similar relative submaximal exercise levels (% peak VO2), the CFS patients portrayed response patterns (trending phenomenon) characterized, in most parameters, by similar intercepts, but either lower (VCO2, HR, O2pulse, VE, VT, PETCO2) or higher (Bf, VE/VCO2) trending kinetics in the CFS compared with the control group. It was found that the primary exercise-related physiological difference between the CFS and the control group was their significantly lower heart rate at any equal relative and at maximal work level. Assuming maximal effort by all (indicated by RER, PETCO2, and subjective exhaustion), these results could indicate either cardiac or peripheral insufficiency embedded in the pathology of CFS patients.

CONCLUSION: We conclude that indexes from cardiopulmonary exercise testing may be used as objective discriminatory indicators for evaluation of patients complaining of chronic fatigue syndrome.


Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S J Intern Med., 2005 Mar;257(3):299-310. From the Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Faculte de Medecine, Institut Federatif de Recherche Jean Roche, and Service des Explorations Fonctionnelles Respiratoires, Hopital Nord, Assistance Publique-Hopitaux de Marseille, Marseille, France. NLM Citation: PMID: 15715687

Abstract.
Objectives.
Because the muscle response to incremental exercise is not well documented in patients suffering from chronic fatigue syndrome (CFS), we combined electrophysiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise. Design. This case-control study compared 15 CFS patients to a gender-, age- and weight-matched control group (n = 11) of healthy subjects. Interventions. All subjects performed an incremental cycling exercise continued until exhaustion. Main outcome measures. We measured the oxygen uptake (Vo(2)), heart rate (HR), systemic blood pressure, percutaneous O(2) saturation (SpO(2)), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO(2) (PvO(2)), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA). Results. Compared with control, in CFS patients (i) the slope of Vo(2) versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO(2) fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period. Conclusions. The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.


*O* Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Black CD, O'Connor PJ, McCully KK. Dynamic Medicine, 2005 Mar 3;4(1):3 The Department of Exercise Science, The University of Georgia, Athens, GA, USA NLM Citation: PMID: 15745455

Abstract:
Individuals with chronic fatigue syndrome (CFS) have been shown to have reduced activity levels associated with heightened feelings of fatigue. Previous research has demonstrated that exercise training has beneficial effects on fatigue-related symptoms in individuals with CFS. PURPOSE: The aim of this study was to sustain an increase in daily physical activity in CFS patients for 4 weeks and assess the effects on fatigue, muscle pain and overall mood. METHOD: Six CFS and seven sedentary controls were studied. Daily activity was assessed by a CSA accelerometer. Following a two week baseline period, CFS subjects were asked to increase their daily physical activity by 30% over baseline by walking a prescribed amount each day for a period of four weeks. Fatigue, muscle pain and overall mood were reported daily using a 0 to 100 visual analog scale and weekly using the Profile of Mood States (Bipolar) questionnaire. RESULTS: CFS patients had significantly lower daily activity counts than controls (162.5 ± 51.7 x 103 counts/day vs. 267.2 ± 79.5 x 103 counts/day) during a 2-week baseline period. At baseline, the CFS patients reported significantly (P < 0.01) higher fatigue and muscle pain intensity compared to controls but the groups did not differ in overall mood. CFS subjects increased their daily activity by 28 ± 19.7% over a 4 week period. Overall mood and muscle pain worsened in the CFS patients with increased activity. CONCLUSIONS: CFS patients were able to increase their daily physical activity for a period of four weeks. In contrast to previous studies fatigue, muscle pain, and overall mood did not improve with increased activity. Increased activity was not presented as a treatment which may account for the differential findings between this and previous studies. The results suggest that a daily "activity limit" may exist in this population. Future studies on the impact of physical activity on the symptoms of CFS patients are needed.


Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Department of Human Physiology, Faculty of Physical Education and Physical Therapy Science, Vrije Universiteit Brussel, Brussel 1090, Belgium. jo.nijs@vub.ac.be

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.


Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). Snell CR, Vanness JM, Strayer DR, Stevens SR. University of the Pacific, Department of Sport Sciences, Stockton, CA 95211-0197, USA. snells@juno.com

Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects. Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.


*O* Chronic Fatigue Syndrome May Be An Infectious Cardiomyopathy Of Single Or Multiple Viral Etiology by Maryann Spurgin, Ph.D.

The most acutely perceptive and pioneering work on CFS these days is happening in a quiet corner of the country, out of the CFS limelight. The work is being conducted by A. Martin Lerner, M.D., an infectious-disease specialist at Wayne State University, along with his colleagues in cardiology. The basic thesis of their well-documented research is that CFS is an infectious cardiomyopathy of single or multiple viral etiology -- a cardiomyopathy that in many cases is progressive and degenerative. According to the theory, CFS results when an initial infection with a virus, or a reactivation of a latent virus -- for example, EBV or CMV -- attacks cardiac tissue, producing exercise intolerance, the hallmark of CFS. The human cardiac myofiber becomes the site of persistent viral infection. The infection flares up when the infected person physically exerts him or herself.

In a normal subject, an ejection fraction will rise during exercise. They note that a stationary or falling ejection fraction is abnormal. Their work cites studies showing that declining ejection fractions are not seen in normal persons leading a sedentary life. Deconditioning and a sedentary lifestyle in normal subjects are not causes of decreasing or falling left ventricular ejection fractions. On the contrary, these cardiac abnormalities are likely virally induced: in some of the CMV patients, ejection fractions reverted to normal after anti-viral therapy with ganciclovir.


Elevated Peroxynitrite as the cause of chronic fatigue syndrome: Other Inducers and Mechanisms of Symptom Generation
Martin L Pall School of Molecular Biosciences, Washington State University, Pullman, WA. Source: J Chronic Fatigue Syndrome 2000; 7(4):45-58.

Abstract: In an earlier paper, I proposed that chronic fatigue syndrome (CFS) is caused by a response to infection, involving the induction of inflammatory cytokines which induce, in turn, the inducible nitric oxide synthase, producing elevated nitric oxide. Nitric oxide reacts with superoxide to form the potent oxidant, peroxynitrite. Six positive feedback loops were proposed by which peroxynitrite may stay elevated, acting to increase levels of both nitric oxide and superoxide, which react to form more peroxynitrite. This vicious cycle based on known biochemistry is proposed to be the central cause of CFS. The current paper discusses additional inducers which may act by increasing nitric oxide (physical or psychological trauma) or increasing superoxide (hypoxia) and the role of orthostatic intolerance, Ehlers-Danlos syndrome, excessive exercise, exercise intolerance and carbon monoxide in inducing hypoxia and consequently superoxide and peroxynitrite. The major symptoms of CFS can all be interpreted as relatively direct consequences of the pathophysiology predicted by the elevated peroxynitrite theory of CFS. Attractive mechanisms are proposed by which elevated peroxynitrite, nitric oxide and/or related physiological changes may induce CFS symptoms including fatigue, immune dysfunction, learning and memory dysfunction, multi-organ pain, exercise intolerance/postexertional malaise and orthostatic intolerance. Roles are discussed for six factors likely to influence the frequency of CFS induction in response to infection or other inducing events.


Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. CR Snell, JM Vanness, DR Strayer, SR Stevens. Department of Sport Sciences, University of the Pacific, Stockton, CA. Source: In Vivo 2002; 16(2):107-9.

Abstract: The elevated RNase L enzyme activity observed in some Chronic Fatigue Syndrome (CFS) patients may be linked to the low exercise tolerance and functional impairment that typify this disease. The purpose of this investigation was to determine if specific indicators of physical performance can predict abnormal RNase L activity in CFS patients. Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. This measure was employed as the dependent variable in a discriminant function analysis, with peak V02, exercise duration and Karnofsky Performance Scores (KPS) serving as the independent variables. All three variables entered the single significant function (p < 0.001). The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. The results suggest that both exercise testing and the RNase L biomarker have potential to aid in the diagnosis of CFS.


*O* The symptoms of Chronic Fatigue Syndrome are related to abnormal ion channel function Peter O. Behan*, Abhijit Chaudhuri*, Walter S. Watson**, John Pearn***
*University Department of Neurology, Institute of Neurological Sciences and **Department of Nuclear Medicine, Southern General Hospital, Glasgow (UK), ***Department of Child Health, University of Queensland, Brisbane (Australia).
Presented at the American Association for Chronic Fatigue Syndrome Research Conference
October 10-11, 1998 -- Cambridge, Massachusetts

Objective: Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, are periodic, fluctuant and are inducible by physical and mental activities. Chest pain is a common symptom of CFS, like patients with syndrome X, an ion channel disorder. Symptoms in CFS such as fatigue, myalgia and headache bear striking resemblance with neurological disorders that affect ion channel function, such as periodic paralysis and familial hemiplegic migraine. Maintenance of normal transmembrane ionic equilibrium is an active, energy-dependent process, and constitutes an important share of the resting energy expenditure (REE). We wanted to compare and contrast the clinical profile of CFS patients with other neurological disorders that are known to affect ion channel function, and estimate REE in CFS. We also studied the myocardial perfusion in CFS by thallium201 SPECT scans to compare the results with Syndrome X. Methods: All patients who fulfilled the modified CDC criteria for CFS were included in our studies. For investigations that required the administration of radiopharmaceuticals (e.g. cardiac-thallium201 SPECT scans), patients between the age of 18 - 65 years were recruited after informed consent. A comparable group of healthy, sedentary volunteers were tested as controls in the REE study. Results: Fatigue was fluctuant in most patients with CFS. This was induced or worsened by physical activities (exercise), mental stress and chemicals that affect ion channel function (e.g. alcohol, quinine and anaesthetics). Significant perfusion defects were observed in the cardiac-thallium201 SPECT scans in 70% of CFS patients, similar to that described in patients with syndrome X. In a separate study, a significant number of CFS patients were found to have elevated REE as compared to the controls using total body potassium (TBK) as the refererence (REE TBK).4 Conclusion: Abnormal thallium201-cardiac SPECT scans in CFS similar to those described in syndrome X suggest a common mechanism for both these conditions. An abnormality of membrane ion channel function is considered the underlying mechanism in syndrome X. Increased REETBK; in a subgroup of CFS patients suggests that some CFS patients spend more energy in maintaining essential body function at the expense of the energy available for other physical activities. Since 30% of REE is expended to maintain physiological ion gradients in normal health, cell membranes that leak ions increase REETBK Elevated REE and abnormal cardiac perfusion scans in CFS provide the first objective and indirect support to our hypothesis that symptoms in CFS could be the result of an acquired abnormality of the voltage or ligand-gated ion channels. It is possible that such alteration of transmembrane ion traffic could affect normal receptor sensitivity to neurochemicals and neurohormones such as acetylcholine, serotonin or other monoamines, accounting for the neuroendocrine abnormalities previously documented in CFS.


 

 
Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome Russell J M Lane,a Michael C Barrett,b David Woodrow,b Jill Moss,b Robert Fletcher,b Leonard C Archardc a Division of Neuroscience and Psychological Medicine, b Division of Diagnostic and Investigative Sciences, c Division of Biochemical Sciences, Imperial College School of Medicine, Charing Cross Hospital, London, UKJ Neurol Neurosurg Psychiatry 1998;64:362-367

OBJECTIVES To examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with chronic fatigue syndrome in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity.
METHODS Quadriceps needle muscle biopsies were obtained from 105 patients with chronic fatigue syndrome and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET).
RESULTS Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Patients with increased lactate responses to exercise did have significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found. CONCLUSION Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.


 
Nurse, is it ME? Understanding myalgic encephalomyelitis. Dale S Prof Nurse. 1991 Mar;6(6):339-40.

Ignored or dismissed for years, myalgic encephalomyelitis (ME) is now recognised as a genuine illness, and sufferers are recommended strict rest until the symptoms of the virus subside. Public understanding of ME is still uncertain, and nurses are ideally placed to provide practical information and support.


Exercise a health risk for chronic fatigue [syndrome] sufferers

Adelaide scientists have found evidence that exercise programs commonly undertaken by patients with chronic fatigue syndrome (CFS), may actually make the condition worse.


Exercise Capacity in Chronic Fatigue Syndrome.

RESULTS: The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects. The maximal workload and maximal oxygen uptake attained by the patients with CFS were almost half those achieved by the control subjects. Analyzing only those persons who performed a maximal exercise test, similar findings were observed.

CONCLUSIONS: When compared with healthy sedentary women, female patients with CFS show a significantly decreased exercise capacity. This could affect their physical abilities to a moderate or severe extent. Reaching the age-predicted target heart rate seemed to be a limiting factor of the patients with CFS in achieving maximal effort, which could be due to autonomic disturbances.


Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome.

The authors attempted to confirm the consistent report by patients with the CFS of delay in recovery of peripheral muscle function after exercise. They tested the quadriceps muscle group of 10 patients and 10 controls. Recovery was prolonged in the patient group, with a significant difference between the two groups after exercise and after 24 hours. These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.


Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression.

The authors theorized that cognitive and motor responses to vigorous exercise in patients with chronic fatigue syndrome would differ from those in depressed and healthy control, and following their study they made the following conclusions: "patients with CFS show a specific sensitivity to the effects of exertion on effortful cognitive functioning. This occurs despite subjective and objective evidence of effort allocation in chronic fatigue syndrome, suggesting that patients have reduced working memory capacity, or a greater demand to monitor cognitive processes, or both."


Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome.

We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.


Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhance postexercise hypotension.


RESEARCH BREAKTHROUGH: ME/CFS AN INFECTIOUS CARDIOMYOPATHY? by: Philipa D. Corning, Ph.D., B.Sc. (Reviewed and approved by Dr. A. Martin Lerner)

In this study, 100% of the ME/CFS participants showed abnormal oscillating T-waves at 24 hr. holter monitoring and 24% showed weakened function on the left side of the heart (abnormal cardiac dynamics). This is the side of the heart that pumps oxygenated blood to all of the body, except the lungs. Data, gathered from biopsies and a 24-hour electrocardiogram (EKG) Holter monitor, showed that patients exhibited evidence of cardiomyopathy or disease of muscle in the heart.

These researchers tracked EKGs over a 24-hour period with a Holter monitor device and documented abnormal T-waves. This wave measures electrical recovery after contraction of the left ventricle. A normal T-wave should be shaped like the rolling crest of a wave in water. In 100% of ME/CFS patients, Lerner and his associates documented T-wave Inversions and/or T-wave flattenings. This finding is so consistent, they suggest that the Holter results should be included as part of the CDC case definition; it distinguishes ME/CFS patients from those with fatigue or unexplained origin. This research holds the potential to distinguish ME/CFS patients from FM patients, from those with other pain syndromes who do not relapse with exertion, and from those with fatigue associated with depression, which is a group that also does not suffer relapse with exertion. This work offers hard evidence to back up ME/CFS patients' much disbelieved claim that exercise is harmful and causes disease progression in ME/CFS.

In Dr. Lerner's model, the weakened heart is aggravated by physical activity, accounting for the post-exertional sickness and accounting for the post-exertional sickness so common in this disease - including flu symptoms, chills, fevers and increasing weakness. Indeed, the cardiac connection is what is so ground-breaking about this research.

In experiments with mice, Dr. Lerner has shown that raised myocardial coxsackie viral titers accompany physical exertion in the mice. When the heart muscle tissue is infected, overactivity causes death of cardiac tissue and disease progression. This is in direct conflict with the U.S. government research conclusions that ME/CFS disease symptoms are caused by underactivity due to a sedentary lifestyle. Dr. Lerner advises resting the heart in order to "do no harm" and to prevent death of cardiac tissue.

Dr. Lerner and associates also have documented abnormal ejection fractions in ME/CFS. Normally, over half of the blood in the left ventricle is ejected when the left ventricle contracts (part of the heart that pumps oxygenated blood out to the body). In Dr. Lerner's ME/CFS subjects, the ejection fraction is sometimes decreased, an indication that not all the normally-expelled blood leaves the ventricle. Some patients had reduced ejection fractions at rest while others had an ejection fraction that decreased during exercise from 51% to 36%. In a normal subject, the ejection fraction will rise over 5% during exercise. Stationary or falling ejection fraction is abnormal in coronary artery disease or cardiac muscle disease. Declining ejection fractions are not seen in normal persons leading sedentary lives.

These cardiac abnormalities are hypothesized to be virally induced.

This model explains the John Hopkins' finding of Rowe et al in which ME/CFS patients exhibited abnormal response to upright tilt. Lerner argues that it is abnormal cardiac response of cardiomyopathy instead of abnormal neural response. Indeed, Dr. Lerner's thesis explains a myriad of phenomenon that other research has not. For example, it explains why patients relapse with exertion and why only physically active young persons may acquire the disease. It also explains why stress is a major aggravator in this disorder. Stress may aggravate both herpes viruses and heart conditions. It also explains the anti-viral lymphocyte enzyme system, the 2-5 A pathway, suggesting the presence of a chronic infection.

In short, Dr. Lerner's work explains why previously healthy, vigorous young adults fall ill with chronic cardiomyopathy due to viral infection and cannot exercise for fear of causing further heart damage. This is directly opposite to the work of Dr. Stephen Straus at National Institute of Health (NIH) whose theory states that ME/CFS is a psychiatric disorder. This new research of Dr. Lerner et al is both refreshing and insightful. Needless to say, it has also been long awaited.


Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.

Plus a discussion of the text.

Thus, as in inherited muscular dystrophy in which a variety of cellular abnormalities can be accounted for by free radical-mediated damages including abnormal functions of the sarcolemma and an altered activity of membrane-bound enzymes involved in excitation-contraction coupling, an increased level of free radical damage in CFS may be a contributor to the underlying functional defects and symptom presentation. This should promote further researches towards the goal of an effective treatment of CFS-suffering patients.


On the pathophysiology of ME/CFS by Les Simpson, MD

The significance of the concept of 'mean capillary diameter' is that it explains why individuals with similar values for altered red cell shapes do or do not evince symptoms. While the effects on red cell shape of a change in the environment is the same, only those with small capillaries will develop symptoms. As overexertion changes red cell shape in an additive fashion, there will be an accompanying exacerbation of symptoms. It is worth noting that in a CFS patient with SPECT-demonstrated reduced cerebral blood flow in a pre-exercise sample, the cerebral blood flow was further reduced in a post-exercise SPECT scan.


Medical Neurobiology of CFS & FM: May May 7-9, 1993 by Jay Goldstein

It is widely documented that exercise is an exacerbator of CFIDS symptoms. Drs. Mena and Goldstein presented a series of SPECT scans which showed extreme hypoperfusion (reduced blood flow) in the brain following exercise. There appeared to be "holes" where blood would normally be flowing -- the degree of hypoperfusion was astonishing. Even 24 hours later, cerebral blood flow was severely reduced.

Cerebral hypoperfusion is not the only result of exercise intolerance. Drs. Lapp and Goldstein referenced irregular tidal volume rates common in PWCs. Hyperventilation and shallow breathing are frequent results of exertion. Normal controls breathe irregularly at the start of exercise, but respiration becomes regular over time. Dr. Lapp reported that PWCs breathed more regularly than controls at the outset, but during exercise their breathing was more variable. Dr. Goldstein concurred, "This phenomenon has never been described before in any population and, as of now anyway, we think that it's a diagnostic marker for CFS."

Neuroendocrine responses were often reversed or blunted in the Cheney-Lapp study. Cortisol, epinephrine, norepinephrine, DHEA levels and body temperature normally rise with exercise, but PWCs were found to have lower than expected measures of all of the above. Dr. Goldstein related this phenomenon to limbic dysfunction, as altered levels of interleukins and nitric oxide (NO) can result in altered neuroendocrine responses to exercise.

Dr. Lapp and Dr. Kathy Sietsema reported that PWCs reached anaerobic threshold much sooner than predicted. Anaerobic threshold (AT) is the point at which a healthy person becomes completely fatigued and cannot exercise any longer (commonly called "hitting the wall"). In the Cheney-Lapp study, PWCs continued exercising beyond the point of AT. Dr. Cheney has hypothesized that PWCs normally perform above AT in everyday activity due to a metabolic injury, and therefore are more accustomed to performing at this level than controls.


Dr. Les Simpson – Rethinking the Pathogenesis of CFIDS By Craig Maupin at http:///www.cfidsreport.com

Simpson continues, "I found that ME blood filtered poorly - implying that they had a problem with blood flow, particularly at capillary level. In a paper published by New Jersey Medicine, I suggested that ME people might have the anatomical feature of smaller than usual capillary diameters. Such a proposal would help to explain the great variety and variation in distribution of the symptoms reported by ME people."

Other models for the illness have struggled to fit the distinct features of CFIDS, such as exertion intolerance and circulatory dysfunction. Simpson feels impaired blood flow offers a unifying thesis that can explain many of these distinct symptoms. He vividly recalls the unique response to exercise of a patient referred to him. "Two scans were done [SPECT scans] -- pre and post exercise. While the pre-exercise scan showed reduced cerebral blood flow, this was much worse in the post-exercise scan. At that time, the effects of physical activity on red cell shape had not been reported. This shows the extent of ignoring blood rheology factors as determinants of blood flow."


*O* CRITICAL CONSIDERATIONS by Margaret Williams

Since as long ago as 1996 it has been known that those with ME / CFS have abnormal lung function tests, with a significant reduction in all lung function parameters tested (see "Lung function test findings in patients with chronic fatigue syndrome" De Lorenzo et al. Australia and New Zealand Journal of Medicine 1996:26:4:563-564), and Jo Nijs from Belgium presented evidence at the Wisconsin international conference of underlying lung damage in ME / CFS through intracellular immune dysregulation with impairment of cardiopulmonary function.

How can forced aerobic exercise regimes be guaranteed to be harmless where there is existing underlying lung damage?


Montague/Hooper paper by Sally Montague, Malcolm Hooper

Tests of exercise capacity

Investigation of exercise capacity (VO2 max) ie. measurement of maximal oxygen uptake and investigation of oxygen delivery to muscle are essential in patients with ME/CFS; oxidative metabolism is known to be reduced in ME/CFS. (78) This could affect patients’ physical abilities to a severe degree. ME/CFS patients have recovery rates for oxygen saturation that are 60% lower than normal controls. (79) It is imperative to ascertain oxygen delivery status before insisting on inappropriate interventions eg. CBT / graded exercise.


Exercise limits in chronic fatigue syndrome [Letter]. Lapp CW. American Journal of Medicine 1997; 103(1): 83-84.


Repetitively negative changing T waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome - left ventricular dysfunction in a cohort. Lerner AM, Lawrie C, Dworkin HS. Chest 1993; 104(5): 1417-21.

Abstract: This study surveys the occurrence of repetitively negative to flat T waves, alternating with normal upright T waves in 24-h electrocardiographic recordings from a subspecialty infectious diseases outpatient practice during the years 1982 to 1990. Patients with normal resting electrocardiogram in the assayed leads, but with repetitively inverted to isoelectric abnormal T waves at Holter monitors, were considered to have abnormal readings. A total of 300 patients had undergone a 24-h Holter monitor. This group included 24 individuals with chronic fatigue syndrome (CFS). This population was restricted to individuals 50 years old or younger, and the patients with CFS are compared with the patients without CFS. One of the more striking differences between the two groups was the difference in abnormal Holter readings. The patients with CFS all had abnormal Holter readings, while 22.4 percent patients without CFS had abnormal readings (p < 0.01). We further report the occurrence of mild left ventricular dysfunction in 8 of 60 patients in continuing studies of this population with CFS, younger than 50 years old, and with no risk factors for coronary artery disease. All 60 patients with CFS showed repetitively flat to inverted T waves alternating with normal T waves. Stress multiple gated acquisitions (MUGAs) (labeled erythrocytes with stannous pyrophosphate) were abnormal in eight patients with CFS. Although resting ejection fractions (EFs) were normal (mean, 60 percent), with increasing work loads (Kilopon meters [Kpms]), gross left ventricular dysfunction occurred. The fatigue of patients with CFS may be related to subtle cardiac dysfunction occurring at work loads common to ordinary living.


The relationship between neurally mediated hypotension and the chronic fatigue syndrome. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. Journal of the American Medical Association 1995; 274(12): 961-7.

Abstract: OBJECTIVE-To compare the clinical symptoms and response evoked by upright tilt-table testing in healthy individuals and in a sample of those satisfying strict criteria for chronic fatigue syndrome. DESIGN-Case-comparison study with mean (SD) follow-up of 24 (5) weeks. SETTING-Tertiary care hospital. PATIENTS AND OTHER PARTICIPANTS-A sample of 23 patients with chronic fatigue syndrome (five men and 18 women; mean age, 34 years), each of whom fulfilled the strict diagnostic criteria of the Centers for Disease Control and Prevention, was recruited from regional chronic fatigue support groups and from the investigators' clinical practices. There were 14 healthy controls (four men and 10 women; mean age, 36 years). INTERVENTIONS-Each subject completed a symptom questionnaire and underwent a three-stage upright tilt-table test (stage 1, 45 minutes at 70 degrees tilt; stage 2, 15 minutes at 70 degrees tilt with 1 to 2 micrograms/min of isoproterenol; and stage 3, 10 minutes at 70 degrees with 3 to 4 micrograms/min of isoproterenol). Patients were offered therapy with fludrocortisone, beta-adrenergic blocking agents, and disopyramide, alone or in combination, directed at neurally mediated hypotension. MAIN OUTCOME MEASURES-Response to upright tilt and scores on symptom questionnaires prior to and during follow-up. RESULTS-An abnormal response to upright tilt was observed in 22 of 23 patients with chronic fatigue syndrome vs four of 14 controls (P < .001). Seventy percent of chronic fatigue syndrome patients, but no controls, had an abnormal response during stage 1 (P < .001). Nine patients reported complete or nearly complete resolution of chronic fatigue syndrome symptoms after therapy directed at neurally mediated hypotension. CONCLUSIONS-We conclude that chronic fatigue syndrome is associated with neurally mediated hypotension and that its symptoms may be improved in a subset of patients by therapy directed at this abnormal cardiovascular reflex.


Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. De Lorenzo F, Hargreaves J, Kakkar VV. Clinical Autonomic Research 1997; 7(4): 185-90.

Abstract: The relationship between orthostatic hypotension and chronic fatigue syndrome (CFS) has been reported previously. To study the pathogenesis and management of delayed orthostatic hypotension in patients with CFS, a case comparison study with follow-up of 8 weeks has been designed. A group of 78 patients with CFS (mean age 40 years; 49% men and 51% women), who fulfilled the Centre for Disease Control and Prevention criteria were studied. There were 38 healthy controls (mean age 43 years; 47% men and 53% women). At entry to the study each subject underwent an upright tilt-table test, and clinical and laboratory evaluation. Patients with orthostatic hypotension were offered therapy with sodium chloride (1200 mg) in a sustained-release formulation for 3 weeks, prior to resubmission to the tilt-table testing, and clinical and laboratory evaluation. An abnormal response to upright tilt was observed in 22 of 78 patients with CFS. After sodium chloride therapy for 8 weeks, tilt-table testing was repeated on the 22 patients with an abnormal response at baseline. Of these 22 patients, 10 redeveloped orthostatic hypotension, while 11 did not show an abnormal response to the test and reported an improvement of CFS symptoms. However, those CFS patients who again developed an abnormal response to tilt-test had a significantly reduced plasma renin activity (0.79 pmol/ml per h) compared both with healthy controls (1.29 pmol/ml per h) and with those 11 chronic fatigue patients (1.0 pmol/ml per h) who improved after sodium chloride therapy (p = 0.04). In conclusion, in our study CFS patients who did not respond to sodium chloride therapy were found to have low plasma renin activity. In these patients an abnormal renin-angiotensin-aldosterone system could explain the pathogenesis of orthostatic hypotension and the abnormal response to treatment.


Possible relationship between chronic fatigue and postural tachycardia syndromes. De Lorenzo F, Hargreaves J, Kakkar VV. Clinical Autonomic Research 1996; 6: 263-264.

Abstract: Postural tachycardia syndrome refers to the development of symptoms such as light-headedness, visual blurring, palpitations and weakness on assuming an upright posture; these symptoms are relieved by resuming a supine posture. This syndrome is occasionally associated with idiopathic hypovolemia, impaired vasomotor tone, deconditioning and autonomic neuropathy, but has not been reported in association with chronic fatigue syndrome (CFS). We describe five patients who satisfied the CFS criteria of the Centres for Disease Control and Prevention. Upright tilt-table testing induced significant hypotension and increased heart rate in all five patients, consistent with clinical and autonomic manifestation of postural tachycardia syndrome.


Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Bazelmans E, Bleijenberg G, Van Der Meer JW, Folgering H. Department of Medical Psychology, University of Nijmegen, The Netherlands.

BACKGROUND: Chronic fatigue syndrome (CFS) patients often complain that physical exertion produces an increase of complaints, leading to a greater need for rest and more time spent in bed. It has been suggested that this is due to a bad physical fitness and that physical deconditioning is a perpetuating factor in CFS. Until now, studies on physical deconditioning in CFS have shown inconsistent results. METHODS: Twenty CFS patients and 20 matched neighbourhood controls performed a maximal exercise test with incremental load. Heart rate, blood pressure, respiratory tidal volume, O2 saturation, O2 consumption, CO2 production, and blood-gas values of arterialized capillary blood were measured. Physical fitness was quantified as the difference between the actual and predicted ratios of maximal workload versus increase of heart rate. Fatigue, impairment and physical activity were assessed to study its relationship with physical fitness. RESULTS: There were no statistically significant differences in physical fitness between CFS patients and their controls. Nine CFS patients had a better fitness than their control. A negative relationship between physical fitness and fatigue was found in both groups. For CFS patients a negative correlation between fitness and impairment and a positive correlation between fitness and physical activity was found as well. Finally, it was found that more CFS patients than controls did not achieve a physiological limitation at maximal exercise. CONCLUSIONS: Physical deconditioning does not seem a perpetuating factor in CFS.


Complement activation in a model of chronic fatigue syndrome.
Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF
. Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA.

BACKGROUND: A need exists to identify biological markers in chronic fatigue syndrome (CFS). OBJECTIVE: To use an exercise and/or allergen challenge to induce the symptoms of CFS and to identify a biological marker that correlates with these symptoms. METHODS: Patients with CFS (n = 32) and age-matched, normal control patients (n = 29) exercised for 20 minutes on a stationary bike at 70% of their predicted max work load (Watts). Patients from each group with positive skin test results were also challenged with intranasally administered relevant allergens. Symptoms were recorded for 2 weeks before and 1 week after each challenge, using 3 different instruments. Blood samples were taken before, and 0, 1, 6, and 24 hours after challenges. Levels of complement split products, cell-associated cytokines, and eosinophilic cationic protein were measured. Mean preexercise and postexercise symptom scores were evaluated for each group. RESULTS: Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (P <.01), regardless of allergy status. Mean symptom scores were significantly increased after exercise through the use of a daily diary (P <.03) and a weekly diary (P <.01) for the CFS group only. Mean scores for the Multidimensional Fatigue Inventory categories "reduced activity" and "mental fatigue" were significantly increased in the CFS group only (P <.04 and P <.02, respectively). CONCLUSIONS: Exercise challenge may be a valuable tool in the development of diagnostic criteria and tests for CFS. Establishment of a role for complement activation products as markers or participants in production of illness require further study.
 

 
Exercise lowers pain threshold in chronic fatigue syndrome. Whiteside A, Hansen S, Chaudhuri A. Departments of Clinical Physics, Institute of Neurological Sciences, South Glasgow University Hospitals NHS Trust, Glasgow, UK.

Post-exertional muscle pain is an important reason for disability in patients who are diagnosed to have Chronic Fatigue Syndrome (CFS). We compared changes in pain threshold in five CFS patients with five age and sex matched controls following graded exercise. Pain thresholds, measured in the skin web between thumb and index finger, increased in control subjects with exercise while it decreased in the CFS subjects. Increased perception of pain and/or fatigue after exercise may be indicative of a dysfunction of the central anti-nociceptive mechanism in CFS patients.
 

 
Altered central nervous system signal during motor performance in chronic fatigue syndrome. Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

OBJECTIVE: The purpose of this study was to determine whether brain activity of chronic fatigue syndrome (CFS) patients during voluntary motor actions differs from that of healthy individuals. METHODS: Eight CFS patients and 8 age- and gender-matched healthy volunteers performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 s rest between adjacent trials--'Non-Fatigue' (NFT) task. Subsequently, the same number of contractions was performed with only a 5 s rest between trials--'Fatigue' (FT) task. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related cortical potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions. RESULTS: Major findings include: (i) Motor performance of the CFS patients was poorer than the controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group (P < 0.05). (iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the NP was greater for the FT than NFT task (P<0.01), whereas no such difference between the two tasks was found in the control group. CONCLUSIONS: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. SIGNIFICANCE: Physical activity-induced EEG signal changes may serve as physiological markers for more objective diagnosis of CFS.

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

He writes:

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