Articles sorted by topic: General M.E. articles and research overviews, The outbreaks (and infectious nature) of M.E., The severity of M.E. and M.E. fatalities. Click here to read the full list of topics available.
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Read Putting research and articles into context and A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy
Before reading the research/advocacy information given in the links below, please be aware of the following facts: 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.
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.
The Nightingale Definition of Myalgic Encephalomyelitis (M.E.) by Dr Byron Hyde 2006
Preface
Since the Nightingale Research Foundation's publication in 1992 of its textbook, The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, there has been a tendency by some individuals and organizations to assume that M.E. and CFS are the same illness. Over the course of two International Association of Chronic Fatigue Syndrome (IACFS, formerly the American Association of CFS) conferences, there have been suggestions that the name CFS be changed to M.E., while retaining the CFS definitions as a basis for such change. This does not seem to me to be a useful initiative: it would simply add credence to the mistaken assumption that M.E. and CFS represent the same disease processes. They do not.
M.E. is a clearly defined disease process. CFS by definition has always been a syndrome
At one of the meetings held to determine the 1994 U.S. Centers for Disease Control and Prevention (CDC) definition of CFS, in response to my question from the floor, Dr. Keiji Fukuda stated that numerous M.E. epidemics he cited the Los Angeles County Hospital epidemic of 1934, the Akureyri outbreak of 1947-48 and the 1955-58 Royal Free Hospitals epidemics-- were definitely not CFS epidemics. Dr. Fukuda was correct.
[Contains details of the many absnormalities seen in M.E., and explains how these can be tested for.]
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 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 absnormalities seen in M.E., and explains how these can be tested for.]
Time to put the exercise cure to rest? by Dr Elizabeth Dowsett
There is ample evidence that M.E. is primarily a neurological illness. It is classified as such under the WHO international classification of diseases (ICD 10, 1992) although non neurological complications affecting the liver, cardiac and skeletal muscle, endocrine and lymphoid tissues are also recognised. Apart from secondary infection, the commonest causes of relapse in this illness are physical or mental over exertion 1. And, on follow up over decades (rather than weeks or months), the average person so disabled is found to be functioning (as a student, employee or parent for example) dangerously near their energy limits. The prescription of increasing exercise is such a situation (or in the early stage of the illness when the patient desperately needs rest) can only be counter-productive.
[In other words - YES!]
The Late Effects of ME by Dr Elizabeth Dowsett
"The number likely to be affected by the post-polio syndrome has been calculated as between 200-270/100,000 currently[7], but no account has been taken of survivors from non-paralytic polio which could easily double that figure. Possible costing for ME support has been based on 3 times the cost of maintenance for multiple sclerosis on the supposition that ME is 3 times as common[4]. The only costs that we can be sure of are those derived from the failure of appropriate management, and of inappropriate assessments which waste vast sums of money and medical time while allowing patients to deteriorate unnecessarily.[16]
Research workers must be encouraged and appropriately funded to work in this field. However they should first be directed to papers published before 1988, the time at which all specialised experience about poliomyelitis and associated infections seem to have vanished mysteriously![11,12,13]"
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:
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]).
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.
*O* Alterations in muscles of CFS patients at morphological, biochemical and molecular level. Pizzigallo E, Di Girolamo A, Montanari G, Dragani L, Vecchiet J, Calella G. Journal of Chronic Fatigue Syndrome 1996; 2(2/3) 76-77.
Abstract: OBJECTIVES. The peripheral origin of symptoms related to CFS has been hypothesized from various AA and is still under investigation to determine if symptoms can be related to muscular damage. Our studies aimed to look for specific alterations in muscles of CFS patients, followed in our Clinic and enrolled according to the 1988 CDC criteria (Holmes et al.) revised in 1994 by Fukuda et al. (CDC). METHODS. Fourteen CFS patients, 3 male and 11 females, 17 to 60 years old (mean 34.6), mean illness duration 49.9 months, post viral onset in 10 cases, underwent muscular biopsy of the vastus lateralis according to Edwards, et al., using a UCH needle. We analyzed the specimens by electron (EM) and light (LM) microscopy. Moreover, we performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA (mtDNA) deletions. RESULTS. All specimens showed: hypotrophy, especially of the type 11 (a and b) fibres; fibres fragmentation, red ragged fibres and fusion events with nuclei centralisation; and fatty and fibrous degeneration. EM observations confirmed these alterations, showed degenerative changes in the I band, and allowed us to detect the poli/pleiomorphism and cristae thickening of the mitochondia. The alterations of the fibres always began from an I band of a sarcomere. The histochemical and quantitative determination of the enzymatic activities showed important reduction, in particular of the cytochrome-oxydase and citrate-synthetase. Finally, the "common deletion" of 4977 bp of the mtdna was increased as high as 3,000 times the normal values in 3 patients. CONCLUSIONS. Our results agree with those of other AA (Behan et al., 1991; Gow et al., 1994). The alterations are compatible with a myopathy of probable mitochondrial origin. This could explain the drop in the functional capability of the muscle as a reduction in potency but, above all, as a reduction in resistance. In conclusion, even if CFS seems to be attributable to mitochondrial and/or muscular alterations, a damage in the central nervous system cannot be excluded. This could explain the neurophychological, behavioral, and neuroendocrinological alterations often found in these patients.
Dr. Paul Cheney on Mitochondrial Myopathy, MRS Brain Scans and Chronic Fatigue Syndrome by Carol Sieverling
CFS ‘a mitochondrial disease’
I asked Cheney about mitochrondrial myopathy and CFS. He confirmed what I suspected: in CFS there is so much injury to the mitochondria that CFS could be called a mitochrondrial disease.
I recall seeing a photo Cheney showed me at my first visit in '96. A study of mitochondria in CFS patients was done at UNC. The photo showed a mitochondria from a healthy person. It was lit up like a thunderstorm on a radar screen - some blues and greens, but a lot of yellow and red – high energy production. The mitochondria from the CFS patients was such a contrast: mostly blues and green with a tiny bit of yellow in it. No where near the energy being produced.
The Heart of the Matter: CFS and Cardiac Issues - Dr Paul Cheney by by Carol Sieverling
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Etiology (Cause)
What is the etiology, the cause, of this cardiac output problem? The short version is that cardiac muscles have lost power because their mitochondria are dysfunctional. They're not functioning well because of a redox-state problem. [Redox: a reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction. Look for a future article explaining redox states.]
*O* Profits Before Patients? Eileen Marshall and Margaret Williams, 15th April 2005
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, s/he can still think and make great demands on the brain, and energy is energy, whether it is being used physically or cognitively.
*O* CRITICAL CONSIDERATIONS by Margaret Williams, 1st November 2004
The issue is whether or not compulsory exercise regimes and “rehabilitative programmes” may be harmful to those with ME / CFS.
In 1999 Professor Paul Cheney from the US went on record as stating: “The most important thing about exercise is not to have (patients with ME / CFS) 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” (Lecture given in Orlando, Florida at the International Congress of Bioenergetic Medicine, 5th-7th February 1999).
Significantly, there is now further supportive evidence that has emerged from the 7th AACFS International Conference held in Madison, Wisconsin, from 8-10th October 2004: “An analysis of metabolic features using MRSI (magnetic resonance spectroscopy imaging) showed elevated lactate levels, which suggests mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy”.
Given this evidence, how can forced aerobic exercise be beneficial to such patients?
The Three Phases of CFS Dr. Paul Cheney's Theory By Carol Sieverling, May 1999
What does Phase III sound like? "Within my boundaries, I don't feel too bad. I'm pretty comfortable. My problem is that every time I try to exceed those boundaries, I crash. I get worse. So I haul back within my boundaries, and I'm now comfortable again." With the loss of dynamic hormone response, patients cannot cross boundaries. Crossing boundaries requires dynamic response capability, and they no longer have it. In addition to the problems with dynamic hormone response, Phase III may also involve damage to the DNA of energy producing mitochondria. The loss of a portion of mitochondria puts an energy ceiling on patients.The extent of the boundaries can vary among patients, depending on the amount of injury done during the first two phases. By no means is everyone home-bound or bedridden. And there is hope. Dr. Cheney does not believe the endpoint of Phase III is totally fixed. There is a good deal of plasticity to the central nervous system, and there can be significant resuscitation of brain function, and perhaps even the mitochondria may not be completely lost.
How Serious is ME The Committee for Justice and Recognition of M.E.
Metabolic disturbance is another major area of the disease. A key factor is the damage to the mitochondria which leads to the pathological extreme exhaustion. This damage to the principal metabolic source of energy has profound effects throughout the body, starving the muscles, brain and immune system of energy for function and repair. The abnormal metabolism includes altered body chemistry that can also lead to severe chemical sensitivity to general toxification from common exogenous chemicals. Metabolic and chemistry changes for example can also lead to osteoporosis, disc and spinal degeneration.
Most patients may be affected by all these factors to varying degrees. Most patients will have a particular pattern of these symptoms that will predominate their experience.
Acylcarnitine deficiency in chronic fatigue syndrome. Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T.Clin Infect Dis. 1994 Jan;18 Suppl 1:S62-7.Osaka University Medical School, Japan.
One of the characteristic complaints of patients with chronic fatigue syndrome (CFS) is the skeletal muscle-related symptom. However, the abnormalities in the skeletal muscle that explain the symptom are not clear. Herein, we show that our patients with CFS had a deficiency of serum acylcarnitine. As carnitine has an important role in energy production and modulation of the intramitochondrial coenzyme A (CoA)/acyl-CoA ratio in the skeletal muscle, this deficiency might induce an energy deficit and/or abnormality of the intramitochondrial condition in the skeletal muscle, thus resulting in general fatigue, myalgia, muscle weakness, and postexertional malaise in patients with CFS. Furthermore, the concentration of serum acylcarnitine in patients with CFS tended to increase to the normal level with the recovery of general fatigue. Therefore, the measurement of acylcarnitine would be a useful tool for the diagnosis and assessment of the degree of clinical manifestation in patients with CFS.
There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's, Parkinson's, and Lou Gehrig's Disease (ALS). Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP (energy) production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. Although protective nuclear responses such as antioxidant enzymes may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This article's hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and points out many potential therapeutic targets for preventing or ameliorating these diseases. PMID: 9974149
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.
The role of mitochondria in the pathogenesis of neurodegenerative diseases. Manfredi G, Beal MF Department of Neurology and Neuroscience, Weill Medical College of Cornell University and the New York Hospital, Cornell Medical Center, New York 10021, USA. gim2004@mail.med.cornell.edu Brain Pathol 2000 Jul;10(3):462-72
A growing body of evidence indicates that mitochondrial dysfunction may play an important role in the pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source of high energy intermediates, but also of free radicals, it has been suggested that inherited or acquired mitochondrial defects could be the cause of neuronal degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities, and also as a consequence of mutations in nuclear genes directly involved in mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an epiphenomenon, which, nevertheless, could be of importance in precipitating a cascade of events leading to cell death. In either case, understanding the role of mitochondria in the pathogenesis of neurodegenerative diseases could be important for the development of therapeutic strategies in these disorders.
United Mitochondrial Disease Foundation Mission: To promote research and education for the diagnosis, treatment and cure of mitochondrial disorders and to provide support to affected individuals and families.
Skeletal muscle function and mitochondrial function suggests a defect in oxidative metabolism with a residual acceleration of glycolysis in the working skeletal muscles in CFS. There is also reduced oxidative muscle metabolism (shown by MRI), and muscle recovery is delayed.
*O* Alterations in muscles of CFS patients at morphological, biochemical and molecular level. Pizzigallo E, Di Girolamo A, Montanari G, Dragani L, Vecchiet J, Calella G. Journal of Chronic Fatigue Syndrome 1996; 2(2/3) 76-77.
Abstract: OBJECTIVES. The peripheral origin of symptoms related to CFS has been hypothesized from various AA and is still under investigation to determine if symptoms can be related to muscular damage. Our studies aimed to look for specific alterations in muscles of CFS patients, followed in our Clinic and enrolled according to the 1988 CDC criteria (Holmes et al.) revised in 1994 by Fukuda et al. (CDC). METHODS. Fourteen CFS patients, 3 male and 11 females, 17 to 60 years old (mean 34.6), mean illness duration 49.9 months, post viral onset in 10 cases, underwent muscular biopsy of the vastus lateralis according to Edwards, et al., using a UCH needle. We analyzed the specimens by electron (EM) and light (LM) microscopy. Moreover, we performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA (mtDNA) deletions. RESULTS. All specimens showed: hypotrophy, especially of the type 11 (a and b) fibres; fibres fragmentation, red ragged fibres and fusion events with nuclei centralisation; and fatty and fibrous degeneration. EM observations confirmed these alterations, showed degenerative changes in the I band, and allowed us to detect the poli/pleiomorphism and cristae thickening of the mitochondia. The alterations of the fibres always began from an I band of a sarcomere. The histochemical and quantitative determination of the enzymatic activities showed important reduction, in particular of the cytochrome-oxydase and citrate-synthetase. Finally, the "common deletion" of 4977 bp of the mtdna was increased as high as 3,000 times the normal values in 3 patients. CONCLUSIONS. Our results agree with those of other AA (Behan et al., 1991; Gow et al., 1994). The alterations are compatible with a myopathy of probable mitochondrial origin. This could explain the drop in the functional capability of the muscle as a reduction in potency but, above all, as a reduction in resistance. In conclusion, even if CFS seems to be attributable to mitochondrial and/or muscular alterations, a damage in the central nervous system cannot be excluded. This could explain the neurophychological, behavioral, and neuroendocrinological alterations often found in these patients.
Impaired oxygen delivery to muscle in chronic fatigue syndrome. McCully KK, Natelson BH Department of Medicine, Medical College of Pennsylvania and Hahnemann University, Philadelphia, PA 19129, USA. kmccully@coe.uga.edu
Clin Sci (Colch) 1999 Nov;97(5):603-8
The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced oxygen delivery to muscles. Patients with CFS according to CDC (Center for Disease Control) criteria (n=20) were compared with normal sedentary subjects (n=12). Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous-wavelength near-IR spectroscopy. Phosphocreatine resynthesis was measured simultaneously using (31)P magnetic resonance spectroscopy. The time constant of oxygen delivery was significantly reduced in CFS patients after exercise (46.5+/-16 s; mean+/-S.D.) compared with that in controls (29.4+/-6.9 s). The time constant of oxygen delivery was also reduced (20.0+/-12 s) compared with controls (12.0+/-2.8 s) after cuff ischaemia. Oxidative metabolism was also reduced by 20% in CFS patients, and a significant correlation was found between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced in CFS patients compared with that in sedentary controls. This result is consistent with previous studies showing abnormal autonomic control of blood flow. Reduced oxidative delivery in CFS patients could be specifically related to CFS, or could be a non-specific effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result in reduced oxidative metabolism and muscle fatigue, further studies will be needed to address this issue.
*O* Post-viral fatigue syndrome: evidence for underlying organic disturbance in the muscle fibre. Jamal GA, Hansen S. European Neurology 1989; 29: 273-276.
Abstract:
Ten patients with post-viral fatigue syndrome and abnormal serological, virological, immunological and histological studies were examined by the single-fibre electromyographic (EMG) technique after excluding concurrent problems in the neuromuscular system. No abnormality of fibre density was noted but all patients had abnormal jitter values. Very high jitter values were not associated with impulse or concomitant blocking. The findings confirm the organic nature of the disease. A muscle membrane disorder probably arising from defective myogenic enzymes is the likely mechanism for the fatigue and the single-fibre EMG abnormalities. This muscle membrane defect may be due to the effects of a persistent viral infection.*O* Biochemical and muscle studies in patients with acute onset post-viral fatigue syndrome. Preedy VR, Smith DG, Salisbury JR, Peters TJ. Journal of Clinical Pathology 1993; 46(8): 722-6.
Abstract:
AIMS-To investigate in detail various biochemical and pathophysiological indices of muscle pathology in acute onset post-viral fatigue syndrome (PVFS). METHODS-Twenty three patients with PVFS (of mean duration 4.6 years) were subjected to needle biopsy for histomorphometry and total RNA contents. Plasma analysis included serology and creatine kinase activities. Indices of whole body mass were also measured-namely, whole body potassium content and plasma carnosinase activities. RESULTS-About 80% of the patients had serology indicative of persistent enteroviral infection as determined by VP1 antigen assay. Only about 10% of that same group of patients had serological indications of current enterovirus infection by IgM assay; a separate subset of 10% showed antibody changes suggestive of reactivation of Epstein-Barr virus. Quantitative morphometric analysis of skeletal muscle fibres indicated that the quadriceps muscle was normal or displayed only minor abnormalities in 22 patients. The Quetelet's Index (body mass index) and whole-body potassium values (index of lean body mass) were not affected in PVFS. The mean plasma carnosinase and creatinine kinase activities were also generally normal in these patients. The mean muscle RNA composition-mg RNA/mg DNA-was significantly reduced in acute onset PVFS by about 15%. The protein:DNA ratio was not significantly affected. CONCLUSIONS-Patients with acute onset PVFS, therefore, lose muscle protein synthetic potential, but not muscle bulk. Histopathology is consistent with these observations. These perturbations may contribute to the apparent feature of perceived muscle weakness associated with the persistent viral infection in the muscle themselves.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.
In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Chaudhuri A, Behan PO.Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, University of Glasgow, 1345 Govan Road, Glasgow G51 4TF, UK. ac54p@udcf.gla.ac.uk
The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.
Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion fatigue syndrome. Arnold DL, Radda GK, Bore PJ, Styles P, Taylor DJ. Lancet 1984; 1: 1367-9.
Abstract:
A patient with prolonged post-viral exhaustion and excessive fatigue was examined by 31P nuclear magnetic resonance. During exercise, muscles of the forearm demonstrated abnormally early intracellular acidosis for the exercise performed. This was out of proportion to the associated changes in high-energy phosphates. This may represent excessive lactic acid formation resulting from a disorder of metabolic regulation. The metabolic abnormality in this patient could not have been demonstrated by traditional diagnostic techniques.Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome Stefania Fulle (a), Patrizia Mecocci (b), Giorgio Fano (c), Iacopo Vecchiet (d), Alba Vecchini (e), Delia Racciotti (d), Antonio Cherubini (b), Eligio Pizzigallo (d), Leonardo Vecchiet (c), Umberto Senin (b) and M. Flint Beal (f). Address correspondence to: Dr. M. Flint Beal, Chairman, Neurology Department, New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA; Tel: (212) 746-6575; Fax: (212) 746-8532; email: fbeal@mail.med.cornell.edu
Free Radical Biology and Medicine Dec 15, 2000, Vol. 29, No. 12, 1252-59Chronic fatigue syndrome (CFS) is a poorly understood disease characterized by mental and physical fatigue, most often observed in young white females. Muscle pain at rest, exacerbated by exercise, is a common symptom. Although a specific defect in muscle metabolism has not been clearly defined, yet several studies report altered oxidative metabolism. In this study, we detected oxidative damage to DNA and lipids in muscle specimens of CFS patients as compared to age-matched controls, as well as increased activity of the antioxidant enzymes catalase, glutathione peroxidase, and transferase, and increases in total glutathione plasma levels. From these results we hypothesize that in CFS there is oxidative stress in muscle, which results in an increase in antioxidant defenses. Furthermore, in muscle membranes, fluidity and fatty acid composition are significantly different in specimens from CFS patients as compared to controls and to patients suffering from fibromyalgia.
These data support an organic origin of CFS, in which muscle suffers oxidative damage.
Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome.
Jacopo Vecchiet, Francesco Cipollone, Katia Falasca, Andrea Mezzetti, Eligio Pizzigallo, Tonino Bucciarelli, Silvana De Laurentis, Giannapia Affaitati, Domenico De Cesare, Maria Adele Giamberardino. Department of Medicine and Science of Aging, 'G. D'Annunzio' University of Chieti, Italy Source: Neuroscience Letters 2003; 335(3):151-154.
Abstract: In 21 patients with chronic fatigue syndrome (CFS) versus 20 normal subjects, we investigated the oxidant/antioxidant balance and its correlation with muscle symptoms. Patients versus controls showed significantly: lower Lag Phase and Vitamin E (Vit E) concentrations in plasma and low-density lipoproteins (LDL), higher LDL thiobarbituric acid reactive substances (TBARS), higher fatigue and lower muscle pain thresholds to electrical stimulation. A significant direct linear correlation was found between fatigue and TBARS, thresholds and Lag Phase, thresholds and Vit E in plasma and LDL. A significant inverse linear correlation was found between fatigue and Lag Phase, fatigue and Vit E, thresholds and TBARS. Increased oxidative stress and decreased antioxidant defenses are related to the extent of symptomatology in CFS, suggesting that antioxidant supplementation might relieve muscle symptoms in the 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.
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."
Skeletal muscle function and mitochondrial function suggests a defect in oxidative metabolism with a residual acceleration of glycolysis in the working skeletal muscles in CFS. There is also reduced oxidative muscle metabolism (shown by MRI), and muscle recovery is delayed.
Abstract:
BACKGROUND: Previous study of patients with chronic fatigue syndrome (CFS) has demonstrated a markedly reduced dynamic exercise capacity, not limited by cardiac performance and in the absence of clinical neuromuscular dysfunction, suggesting the possibility of a subclinical defect of skeletal muscle. METHODS: The in vivo metabolism of the gastrocnemius muscles of 22 CFS patients and 21 normal control subjects was compared during rest, graded dynamic exercise to exhaustion and recovery, using 31P nuclear magnetic resonance (NMR) spectroscopy to reflect minute-to-minute intracellular high-energy phosphate metabolism. RESULTS: Duration of exercise was markedly shorter in the CFS patients (8.1 ± 2.8 min) compared with the normal subjects (11.3 ± 4.3 min) (p = 0.005). There were large changes in phosphocreatine (PCr), inorganic phosphate (Pi), and pH from rest to clinical fatigue in all subjects, reflecting the high intensity of the exercise. The temporal metabolic patterns were qualitatively similar in the CFS patients and normal subjects. There were early and continuous changes in PCr and Pi that peaked at the point of fatigue and rapidly reversed after exercise. In contrast, pH was relatively static in early exercise, not declining noticeably until 50 percent of total exercise duration was achieved, and reaching a nadir at 2 min postexercise, before rapidly reversing. There were no differences in pH at rest (7.08 ± 0.04 vs 7.10 ± 0.04), exhaustion (6.85 ± 0.17 vs 6.76 ± 0.17) or early (6.64 ± 0.25 vs 6.56 ± 0.24) or late recovery (7.09 ± 0.04 vs 7.10 ± 0.05), CFS patients vs normal subjects, respectively (NS). Neither were there intergroup differences (NS) in PCr or Pi. Although, quantitatively, the changes in PCr, Pi, and pH were marked and similar in both groups from rest to exhaustion, the changes all occurred much more rapidly in the CFS patients. Moreover, adenosine triphosphate (ATP) was significantly (p = 0.007) less at exhaustion in the CFS group. CONCLUSIONS: Patients with CFS and normal control subjects have similar skeletal muscle metabolic patterns during dynamic exercise and reach similar clinical and metabolic end points. However, CFS patients reach exhaustion much more rapidly than normal subjects, at which point they also have relatively reduced intracellular concentrations of ATP. These data suggest a defect of oxidative metabolism with a resultant acceleration of glycolysis in the working skeletal muscles of CFS patients. This metabolic defect may contribute to the reduced physical endurance of CFS patients. Its etiology is unknown. Whether CFS patients' overwhelming tiredness at rest has a similar metabolic pathophysiology or etiology also remains unknown.Abstract:
The decrease in maximal force-generating capacity, the degree of central activation of the muscle, and the subjective perception of effort were measured during prolonged submaximal isometric exercise in 12 male patients suffering from the 'chronic fatigue syndrome' and 13 naive, healthy male subjects. Maximal voluntary isometric torque generated by the elbow flexors was measured before, and at 5 min intervals during an endurance sequence of 45 min of repetitive isometric contractions (6 s duration, 4 s rest interval) producing 30% of the initial maximal voluntary torque. Electrical stimuli were also delivered to the elbow flexors to measure the contractile force in the intervals between voluntary contractions. The degree of central motor activation during maximal voluntary contractions was assessed using a sensitive method of twitch interpolation. In addition, the perceived effort required to achieve the target submaximal contractions was recorded using a standardized self-report scale. A high degree of central activation was achieved in maximal contractions during the endurance sequence both in the patients (mean of maximal force 93.6%; SD 7.8%), and in the control subjects (mean 90.9%; SD 9.5%). The relative torque produced by either voluntary or electrically stimulated contractions was not significantly different between patients and control subjects throughout the test. There was no significant difference in the perceived exertion between the patients and control subjects. These findings support the concept that neither poor motivation, nor muscle contractile failure is important in the pathogenesis of 'fatigue' in patients with the chronic fatigue syndrome.