17 Apr 2005 - Recomended Reading
Permission to Repost
Profits Before Patients?
Eileen Marshall Margaret Williams
15th April 2005
The role of the Medical Research Council (MRC) is to fund projects on
the basis of expertly written, peer-reviewed and approved proposals.
Clearly, therefore, the role of peer-reviewers is of paramount
importance as it is they who influence what research the MRC will
fund.
In the case of ME/ICD-CFS there are a limited number of peer-reviewers
of psychiatric interventions of cognitive behavioural therapy and
graded exercise apart from the PACE trial proponents themselves, so
the favourable recommendation of the carefully selected peer-reviewers
was not unexpected, nor was the decision to fund the trials on
"CFS/ME" patients.
The PACE trials involve compulsory aerobic exercise even though the
deleterious effects of such exercise on those with ME/ICD-CFS are well
documented in the medical literature. It was documented as long ago as
1988 that there was "general agreement that (ME's) distinguishing
characteristic is severe muscle fatiguability, made worse by exercise.
It becomes apparent that any kind of muscle exercise can cause
patients to be almost incapacitated (and) the patient is usually
confined to bed. What is certain is that it becomes plain that this is
an organic illness in which muscle metabolism is severely affected"
(see Crit Rev Neurobiol: 1988:4:2:157-178).
The MRC has resolutely refused to heed submitted concerns from the UK
ME/ICD-CFS community about the potential dangers of the PACE trials to
those with ME/ICD-CFS. Even when sent by Recorded Delivery, these
concerns are not acknowledged, let alone addressed. Personal letters
(also sent by Recorded Delivery) to Professor Colin Blakemore (Chief
Executive) and to Professor Sir Liam Donaldson (Chief Medical Officer
at the Department of Health) also go unacknowledged and unanswered.
Personal meetings with both these Executives arranged by the Countess
of Mar and Earl (Freddie) Howe (Shadow Health Spokesman), at which
these same concerns have been raised, have proved fruitless.
The potential danger is not only because exercise - especially aerobic
exercise -- is known to cause significant general deterioration and
increased pain in ME/ICD-CFS patients: it is because those trials
involve graded aerobic exercise in patients who may have serious
cardiac problems.
Cardiac problems in ME have been documented in the medical literature
for over half a century - the fact that normal loss of blood flow may
be persistent in ME was documented by Gilliam in 1938. Other cardiac
problems have been consistently in the literature since that time, for
example, Wallis (1957); Leon-Sotomayer (1965) and Ramsay
(1950s-1980s), and in his 1988 CIBA Foundation lecture, Professor
Peter Behan from Glasgow confirmed that he was regularly able to
demonstrate micro-capillary perfusion defects in the cardiac muscle of
ME patients. Also in 1988 it was noted that "Evidence of cardiac
involvement may be seen: palpitations, severe tachycardia with
multiple ectopic beats and occasional dyspnoea may occur and are quite
distressing. It is of great interest that some patients have evidence
of myocarditis" (see Crit Rev Neurobiol 1988:4:2:157-178). In 2001, in
her Research Update presentation to the Alison Hunter Memorial
Foundation Third International Clinical and Scientific
Conference on ME/ICD-CFS held in Sydney, Professor Mina Behan from
Glasgow (recently deceased) stated: "Convincing evidence of
cardiovascular impairment can be demonstrated".
[For the early references, see "The Clinical and Scientific Basis of
ME/CFS" edited by Byron Hyde, Jay Goldstein and Paul Levine, published
in 1992 by The Nightingale Research Foundation, Ottawa. See also BMJ
1989:299:1219; Postviral Fatigue Syndrome ed. Rachel Jenkins and James
Mowbray, pub. John Wiley & Sons, 1992; Inf Dis Clin Practice
1997:6:327-333; Proc Soc R Coll Physicians Edinb 1998:28:150-163; Hum.
Psychopharmacol.Clin.Exp 1999:14:7-17; Clin Physiol 1999:19:2:111-120;
JCFS 2001:8:(3-4):107-109].
The difficulty with some of the earlier references is that the
documented clinical observations may not have been scientifically
evaluated: in the current climate which dictates that "evidence-based
medicine" is the only acceptable medicine, such observations are
dismissed and ignored because there is no "evidence-based data". In
the 21st Century, this is called progress in medicine.
Despite the documented evidence of the potential dangers of graded
exercise to those with ME/ICD-CFS, the MRC and its chosen
peer-reviewers (with the regrettable approval of certain ME charities)
seem determined to support the PACE trials and apparently have little
concern for the potential consequences to patients with ME. It seems
that the MRC remains committed to its well-known and long-held
conviction of its former psychiatrist Board Member (Professor Simon
Wessely) that "CFS/ME" is "medically unexplained chronic fatigue" and
is therefore a primary psychiatric disorder, and chooses to disregard
the evidence that disproves such a conviction. It is also the case
that the Government-funded Centres will employ the same psychiatric
interventions of cognitive behavioural therapy and compulsory graded
exercise.
Consequently there are now ever-louder calls for Judicial Review and
for representation to the European Court of Human Rights in
Strasbourg, backed by an eminent Queen's Counsel in the House of
Lords.
It may seem pointless to bring to attention once again the inherent
dangers of graded exercise for those with ME/ICD-CFS, but the recent
update of the paper by Carol Sieverling posted on Co-Cure on 10th
April 2005 ("The Heart of the Matter: CFS and Cardiac Issues" - a 41
page exposition of Dr Paul Cheney's experience and expertise, from
which the following notes are taken and to both of whom grateful
acknowledgement is made) has inspired one further attempt.
Cheney's focus is based on the paper by Dr Ben Natelson (neurologist
and Professor of Neurology) and Dr Arnold Peckerman (cardiopulmonary
physiologist) at New Jersey Medical Centre (ref: "Abnormal Impedance
Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome":
Peckerman et al: The American Journal of the Medical Sciences:
2003:326:(2):55-60).
This important paper says that, without exception, every disabled
CFIDS (ie. ME/ICD-CFS) patient is in heart failure.
There are two kinds of heart failure: one that any cardiologist can
diagnose in about a minute (which CFIDS patients do not have); the
other is Compensated Idiopathic Cardiomyopathy (CIM). Given that at
least 35% of those with CIM will die within 5 years unless they
receive a heart transplant, but given that in 20 years' experience of
CFIDS Cheney has never seen one patient go on to transplant, why
aren't those with CFIDS-induced CIM not dead? Cheney believes it's
because CFIDS itself is protecting patients from a deeper problem that
is often missed because it is so well-hidden.
The problem
The New Jersey team looked at many things in CFIDS patients and they
found something: a "Q" problem. "Q" stands for cardiac output in
litres per minute. In CFIDS 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 that is not experimental.
Normal people pump 7 litres 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 that 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. This is critical to
understanding what Cheney believes happens in CFIDS patients.
However, what the New Jersey team found in people with CFIDS was
astonishing -when disabled CFIDS 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.
Symptoms
The New Jersey team then looked to see if there were any symptoms that
were observable in disabled CFIDS patients but not in others and they
found that there was only one such symptom that was seen in patients
with a Q problem: post-exertional fatigue. To quote Cheney: "That is,
when you push yourself physically, you get worse".
CFIDS patients have a big Q problem; to quote Cheney again: "all
disabled CFIDS patients, all of whom have post-exertional fatigue,
have low Q and are in heart failure".
Post-exertional fatigue (long documented as the cardinal feature of
ME/ICD-CFS but not of other, non-specific, states of chronic fatigue)
is the one symptom that correlates with Q. Among disabled CFIDS
patients, 80% had muscle pain; 75% had joint pain; 72% had memory and
concentration problems; 70% had unrefreshing sleep; 68% had fever and
chills; 62% had generalised weakness; 60% had headaches, but 100% had
post-exertional fatigue.
In Cheney's model, symptoms in CFIDS reflect the interaction between Q
and how the body compensates for too low a Q, so depending on the
nature of the compensation (which is individually distinct), there is
an array of symptoms that is individually determined and which will
arise out of factors unique to each person.
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 a low Q (Q being
cardiac output in litres per minute). This compensation is what is
going on in the CFIDS patient.
In the Peckerman study, the data on the disabled CFIDS patients
reveals that even when they are lying down, their Q is only 5 litres
per minute (not 7 as in normals). When disabled CFIDS patients stand
up, the Q of 5 litres per minute drops to 3.7 litres per minute, so
these patients do not have adequate Q to function. 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.
Compensated Idiopathic Cardiomyopathy
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 ME/ICD-CFS 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 than the liver, the gut, the muscles
and the skin from a drop in Q.
In what order is tissue perfusion sacrificed, and what are the
consequences? Certainly, Cheney's submission seems to tally with the
experience of long-term ME sufferers.
The first is the skin: if the microcirculation of the skin is
compromised, several problems can arise. One is that without adequate
microcirculation to the skin, 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 result of this is that
the patient 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 -- in other words, the patient
develops Multiple Chemical Sensitivity.
The second effect: if things get worse, the next microcirculation to
be sacrificed is that to the muscles and the patient will have
exercise intolerance and s/he cannot go upstairs. If things get still
worse, the patient begins to get fibromyalgic pain in the muscles.
Cheney posits that if microcirculation to the joints becomes
compromised, it may precipitate pyrophosphoric acid and uric acid
crystals and the patient starts to have arthralgia linked to this
circulatory defect.
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 s/he will be able
to tolerate, 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 and / or sensitivities. The
body will be unable to detoxify the gut ecology, so the gut will begin
to poison the patient, who will feel a sense of toxic malaise, with
diarrhoea, constipation, flatulence and all kinds of gut problems. If
this gets worse, a malabsorption syndrome will develop, resulting in
increasing toxicity in which the patient feels "yucky" and which can
manifest as a variety of skin
disturbances (for instance, a rash), as well as problems in the brain.
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.
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": manfestation 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. As it
gets worse, there will be mitral valve prolapse (MVP) because of
inadequate capillary function. Finally, 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 the "event horizon" with respect to
the heart is this: when the microcirculation defect within the heart
itself begins to impact Q itself, 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 is
the lung.
The sixth affected system is the lung and kidney: cardiac failure in
the lung produces Congestive Heart Failure (CHF) 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, which is the requisite cause of
death due to Compensated Idiopathic Cardiomyopathy.
For some interesting reason, there is something about CFIDS that keeps
patients from progressing across the final event horizon, although
Peckerman believes that a certain percentage of CFIDS patients are
heading that way. How will a patient know if s/he eventually loses the
ability to compensate? They will know it if when they lie down, they
are short of breath.
The cause of the cardiac output problem
Cheney's view is that cardiac muscle has lost power because the
mitochondria are dysfunctional due to a redox-state problem. Redox is
a reversible chemical reaction in which one reaction is an oxidation
and the reverse is a reduction.
What causes the redox-state problem? Cheney does not know, but he does
know that in CFIDS, like MCS and Gulf War Syndrome, there is a
redox-state problem. There is, however, something unique in CFIDS,
which is that the redox-state problem seems centred on the heart. In
Cheney's model, candidates include viruses and heavy metals in an
interaction with allergies and toxins.
Cheney then discusses Martin Pall's work and theories relating to the
pathophysiology at the cellular level that he believes underpins this
pathophysiological state (ie. the role of peroxynitrite). Cheney
describes it in simple terms: nitric oxide + superoxide =
peroxynitrite, which is highly damaging. Nitric oxide and superoxide
have to be generated because they are essential for life and are
necessary for energy generation. In health, nitric oxide is found
outside the mitochondria and superoxide is found inside the
mitochondria. In CFIDS, however, superoxide is out of control, so
there are few limits to the formation of peroxynitrite. Using Pall's
model, Cheney accepts that if a person is immune-activated (either
from a virus, or from bacteria, or from toxin exposure), then that
person is generating an excess amount of nitric oxide. Superoxide is
produced by the act of making energy (ATP). If the person is also
making a significant amount of ATP, it can result in superoxide, which
then binds to the nitric oxide to produce large amounts of
peroxynitrite, resulting in major problems with oxygen transport,
microcirculatory impairment and lack of tissue perfusion. To protect
the body from going down the death spiral, it stops making energy,
which results in significant reduction of superoxide and thus of
peroxynitrite.
Cheney discusses various methods of blocking peroxynitrite, including
pharmacological interventions (for example, the blocking of NMDA
reduces nitric oxide) and more basic methods such as increasing carbon
dioxide by re-breathing (carbon dioxide is a primary scavenger of
peroxynitrite). Uric acid is also a powerful scavenger of
peroxynitrite; Cheney has measured uric acid levels in CFIDS patients
and has found them to be amongst the lowest levels he has ever
measured in his entire medical career.
Cheney notes that the best endogenous scavenger of nitric oxide is
haemoglobin (a protein that transports oxygen from the lungs to the
tissues) but that when haemoglobin scavenges nitric oxide, the nitric
oxide bends the haemoglobin, causing the red blood cells to deform. Dr
Les Simpson in New Zealand found that the red blood cells of patients
with CFIDS were deformed and when deformed, they cannot get through
the capillary bed and so cause pain. An indication of such deformity
is a drop in the sedimentation rate (SED, or ESR) and Cheney has
observed that when measured in a laboratory, CFIDS patients'
sedimentation rate is the lowest he has ever recorded, which confirms
to Cheney that CFIDS patients have an induced haemoglobinopathy. He
believes that the CFIDS 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 CFIDS 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's bad enough when patients do not
perfuse their muscles and joints (because of poor microcirculation)
but it's 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 ME/ICD-CFS (an acquired haemoglobinopathy) and the third is
idiopathic cardiomyopathy.
Cheney observes that in order to improve cardiac output in CFIDS,
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. He has
found increasing the intake of potassium to be helpful (potassium
induces aldosterone, a hormone that significantly increases blood
volume), and that magnesium is beneficial as it is a vasodilator and
helps reduce the resistance the blood encounters.
Cheney is at pains to emphasise that none of these measures is a cure
---they are simply means to help patients disabled with CFIDS remain
as functional as possible.
In the UK, the question has to be asked: how can forced aerobic
exercise help such patients remain as functional as possible?
In the light of the Peckerman et al paper that was published in 2003,
are the psychiatrists and their peer reviewers at the MRC who approved
the PACE trial protocol still convinced that these trials (and the
exercise regimes to be meted out by the new Centres) pose no harm for
those with ME/ICD-CFS, or are they content to rely on the certainty
that they themselves can never be held accountable for any harm to any
patient because all participants must sign a compulsory waiver which
means that no participant can ever pursue any claim for medical
negligence or damages?
Another question needs to be asked and urgently answered: would it not
more effectively advance medical and scientific understanding of this
increasingly prevalent and devastating disorder if the MRC were at
last to let it be known that they would look favourably upon
applications for research funding submitted by those in disciplines
other than psychiatry?
Considering the rapidly increasing weight of available published data on organic pathology in ME/ICD-CFS (little of which is published in the UK medical literature), the MRC will inevitably have its hand forced eventually, as the time will come when such evidence can no longer continue to be ignored, but currently this seems to remain a forlorn hope.
Is this because the biomedical issues that have been shown by internationally respected researchers to underpin ME/ICD-CFS are deemed inconvenient in the UK as they do not accord with Government's preferred policy of off-loading as cheaply as possible the ever-increasing hordes of chronically sick who have no commercial value to the State but who cost it far too much money?
Surely this is a short-sighted policy, because it is well recognised that those who are correctly diagnosed and permitted to rest adequately in the initial stages are the ones who have hope of some recovery; moreover, if relevant research were to be instituted, it would lead to patients being investigated competently and treated correctly, thus offering the prospect of ME/ICD-CFS patients being able to return to an economically productive life.
Profits Before Patients?
Eileen Marshall Margaret Williams
15th April 2005
The role of the Medical Research Council (MRC) is to fund projects on
the basis of expertly written, peer-reviewed and approved proposals.
Clearly, therefore, the role of peer-reviewers is of paramount
importance as it is they who influence what research the MRC will
fund.
In the case of ME/ICD-CFS there are a limited number of peer-reviewers
of psychiatric interventions of cognitive behavioural therapy and
graded exercise apart from the PACE trial proponents themselves, so
the favourable recommendation of the carefully selected peer-reviewers
was not unexpected, nor was the decision to fund the trials on
"CFS/ME" patients.
The PACE trials involve compulsory aerobic exercise even though the
deleterious effects of such exercise on those with ME/ICD-CFS are well
documented in the medical literature. It was documented as long ago as
1988 that there was "general agreement that (ME's) distinguishing
characteristic is severe muscle fatiguability, made worse by exercise.
It becomes apparent that any kind of muscle exercise can cause
patients to be almost incapacitated (and) the patient is usually
confined to bed. What is certain is that it becomes plain that this is
an organic illness in which muscle metabolism is severely affected"
(see Crit Rev Neurobiol: 1988:4:2:157-178).
The MRC has resolutely refused to heed submitted concerns from the UK
ME/ICD-CFS community about the potential dangers of the PACE trials to
those with ME/ICD-CFS. Even when sent by Recorded Delivery, these
concerns are not acknowledged, let alone addressed. Personal letters
(also sent by Recorded Delivery) to Professor Colin Blakemore (Chief
Executive) and to Professor Sir Liam Donaldson (Chief Medical Officer
at the Department of Health) also go unacknowledged and unanswered.
Personal meetings with both these Executives arranged by the Countess
of Mar and Earl (Freddie) Howe (Shadow Health Spokesman), at which
these same concerns have been raised, have proved fruitless.
The potential danger is not only because exercise - especially aerobic
exercise -- is known to cause significant general deterioration and
increased pain in ME/ICD-CFS patients: it is because those trials
involve graded aerobic exercise in patients who may have serious
cardiac problems.
Cardiac problems in ME have been documented in the medical literature
for over half a century - the fact that normal loss of blood flow may
be persistent in ME was documented by Gilliam in 1938. Other cardiac
problems have been consistently in the literature since that time, for
example, Wallis (1957); Leon-Sotomayer (1965) and Ramsay
(1950s-1980s), and in his 1988 CIBA Foundation lecture, Professor
Peter Behan from Glasgow confirmed that he was regularly able to
demonstrate micro-capillary perfusion defects in the cardiac muscle of
ME patients. Also in 1988 it was noted that "Evidence of cardiac
involvement may be seen: palpitations, severe tachycardia with
multiple ectopic beats and occasional dyspnoea may occur and are quite
distressing. It is of great interest that some patients have evidence
of myocarditis" (see Crit Rev Neurobiol 1988:4:2:157-178). In 2001, in
her Research Update presentation to the Alison Hunter Memorial
Foundation Third International Clinical and Scientific
Conference on ME/ICD-CFS held in Sydney, Professor Mina Behan from
Glasgow (recently deceased) stated: "Convincing evidence of
cardiovascular impairment can be demonstrated".
[For the early references, see "The Clinical and Scientific Basis of
ME/CFS" edited by Byron Hyde, Jay Goldstein and Paul Levine, published
in 1992 by The Nightingale Research Foundation, Ottawa. See also BMJ
1989:299:1219; Postviral Fatigue Syndrome ed. Rachel Jenkins and James
Mowbray, pub. John Wiley & Sons, 1992; Inf Dis Clin Practice
1997:6:327-333; Proc Soc R Coll Physicians Edinb 1998:28:150-163; Hum.
Psychopharmacol.Clin.Exp 1999:14:7-17; Clin Physiol 1999:19:2:111-120;
JCFS 2001:8:(3-4):107-109].
The difficulty with some of the earlier references is that the
documented clinical observations may not have been scientifically
evaluated: in the current climate which dictates that "evidence-based
medicine" is the only acceptable medicine, such observations are
dismissed and ignored because there is no "evidence-based data". In
the 21st Century, this is called progress in medicine.
Despite the documented evidence of the potential dangers of graded
exercise to those with ME/ICD-CFS, the MRC and its chosen
peer-reviewers (with the regrettable approval of certain ME charities)
seem determined to support the PACE trials and apparently have little
concern for the potential consequences to patients with ME. It seems
that the MRC remains committed to its well-known and long-held
conviction of its former psychiatrist Board Member (Professor Simon
Wessely) that "CFS/ME" is "medically unexplained chronic fatigue" and
is therefore a primary psychiatric disorder, and chooses to disregard
the evidence that disproves such a conviction. It is also the case
that the Government-funded Centres will employ the same psychiatric
interventions of cognitive behavioural therapy and compulsory graded
exercise.
Consequently there are now ever-louder calls for Judicial Review and
for representation to the European Court of Human Rights in
Strasbourg, backed by an eminent Queen's Counsel in the House of
Lords.
It may seem pointless to bring to attention once again the inherent
dangers of graded exercise for those with ME/ICD-CFS, but the recent
update of the paper by Carol Sieverling posted on Co-Cure on 10th
April 2005 ("The Heart of the Matter: CFS and Cardiac Issues" - a 41
page exposition of Dr Paul Cheney's experience and expertise, from
which the following notes are taken and to both of whom grateful
acknowledgement is made) has inspired one further attempt.
Cheney's focus is based on the paper by Dr Ben Natelson (neurologist
and Professor of Neurology) and Dr Arnold Peckerman (cardiopulmonary
physiologist) at New Jersey Medical Centre (ref: "Abnormal Impedance
Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome":
Peckerman et al: The American Journal of the Medical Sciences:
2003:326:(2):55-60).
This important paper says that, without exception, every disabled
CFIDS (ie. ME/ICD-CFS) patient is in heart failure.
There are two kinds of heart failure: one that any cardiologist can
diagnose in about a minute (which CFIDS patients do not have); the
other is Compensated Idiopathic Cardiomyopathy (CIM). Given that at
least 35% of those with CIM will die within 5 years unless they
receive a heart transplant, but given that in 20 years' experience of
CFIDS Cheney has never seen one patient go on to transplant, why
aren't those with CFIDS-induced CIM not dead? Cheney believes it's
because CFIDS itself is protecting patients from a deeper problem that
is often missed because it is so well-hidden.
The problem
The New Jersey team looked at many things in CFIDS patients and they
found something: a "Q" problem. "Q" stands for cardiac output in
litres per minute. In CFIDS 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 that is not experimental.
Normal people pump 7 litres 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 that 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. This is critical to
understanding what Cheney believes happens in CFIDS patients.
However, what the New Jersey team found in people with CFIDS was
astonishing -when disabled CFIDS 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.
Symptoms
The New Jersey team then looked to see if there were any symptoms that
were observable in disabled CFIDS patients but not in others and they
found that there was only one such symptom that was seen in patients
with a Q problem: post-exertional fatigue. To quote Cheney: "That is,
when you push yourself physically, you get worse".
CFIDS patients have a big Q problem; to quote Cheney again: "all
disabled CFIDS patients, all of whom have post-exertional fatigue,
have low Q and are in heart failure".
Post-exertional fatigue (long documented as the cardinal feature of
ME/ICD-CFS but not of other, non-specific, states of chronic fatigue)
is the one symptom that correlates with Q. Among disabled CFIDS
patients, 80% had muscle pain; 75% had joint pain; 72% had memory and
concentration problems; 70% had unrefreshing sleep; 68% had fever and
chills; 62% had generalised weakness; 60% had headaches, but 100% had
post-exertional fatigue.
In Cheney's model, symptoms in CFIDS reflect the interaction between Q
and how the body compensates for too low a Q, so depending on the
nature of the compensation (which is individually distinct), there is
an array of symptoms that is individually determined and which will
arise out of factors unique to each person.
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 a low Q (Q being
cardiac output in litres per minute). This compensation is what is
going on in the CFIDS patient.
In the Peckerman study, the data on the disabled CFIDS patients
reveals that even when they are lying down, their Q is only 5 litres
per minute (not 7 as in normals). When disabled CFIDS patients stand
up, the Q of 5 litres per minute drops to 3.7 litres per minute, so
these patients do not have adequate Q to function. 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.
Compensated Idiopathic Cardiomyopathy
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 ME/ICD-CFS 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 than the liver, the gut, the muscles
and the skin from a drop in Q.
In what order is tissue perfusion sacrificed, and what are the
consequences? Certainly, Cheney's submission seems to tally with the
experience of long-term ME sufferers.
The first is the skin: if the microcirculation of the skin is
compromised, several problems can arise. One is that without adequate
microcirculation to the skin, 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 result of this is that
the patient 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 -- in other words, the patient
develops Multiple Chemical Sensitivity.
The second effect: if things get worse, the next microcirculation to
be sacrificed is that to the muscles and the patient will have
exercise intolerance and s/he cannot go upstairs. If things get still
worse, the patient begins to get fibromyalgic pain in the muscles.
Cheney posits that if microcirculation to the joints becomes
compromised, it may precipitate pyrophosphoric acid and uric acid
crystals and the patient starts to have arthralgia linked to this
circulatory defect.
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 s/he will be able
to tolerate, 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 and / or sensitivities. The
body will be unable to detoxify the gut ecology, so the gut will begin
to poison the patient, who will feel a sense of toxic malaise, with
diarrhoea, constipation, flatulence and all kinds of gut problems. If
this gets worse, a malabsorption syndrome will develop, resulting in
increasing toxicity in which the patient feels "yucky" and which can
manifest as a variety of skin
disturbances (for instance, a rash), as well as problems in the brain.
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.
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": manfestation 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. As it
gets worse, there will be mitral valve prolapse (MVP) because of
inadequate capillary function. Finally, 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 the "event horizon" with respect to
the heart is this: when the microcirculation defect within the heart
itself begins to impact Q itself, 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 is
the lung.
The sixth affected system is the lung and kidney: cardiac failure in
the lung produces Congestive Heart Failure (CHF) 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, which is the requisite cause of
death due to Compensated Idiopathic Cardiomyopathy.
For some interesting reason, there is something about CFIDS that keeps
patients from progressing across the final event horizon, although
Peckerman believes that a certain percentage of CFIDS patients are
heading that way. How will a patient know if s/he eventually loses the
ability to compensate? They will know it if when they lie down, they
are short of breath.
The cause of the cardiac output problem
Cheney's view is that cardiac muscle has lost power because the
mitochondria are dysfunctional due to a redox-state problem. Redox is
a reversible chemical reaction in which one reaction is an oxidation
and the reverse is a reduction.
What causes the redox-state problem? Cheney does not know, but he does
know that in CFIDS, like MCS and Gulf War Syndrome, there is a
redox-state problem. There is, however, something unique in CFIDS,
which is that the redox-state problem seems centred on the heart. In
Cheney's model, candidates include viruses and heavy metals in an
interaction with allergies and toxins.
Cheney then discusses Martin Pall's work and theories relating to the
pathophysiology at the cellular level that he believes underpins this
pathophysiological state (ie. the role of peroxynitrite). Cheney
describes it in simple terms: nitric oxide + superoxide =
peroxynitrite, which is highly damaging. Nitric oxide and superoxide
have to be generated because they are essential for life and are
necessary for energy generation. In health, nitric oxide is found
outside the mitochondria and superoxide is found inside the
mitochondria. In CFIDS, however, superoxide is out of control, so
there are few limits to the formation of peroxynitrite. Using Pall's
model, Cheney accepts that if a person is immune-activated (either
from a virus, or from bacteria, or from toxin exposure), then that
person is generating an excess amount of nitric oxide. Superoxide is
produced by the act of making energy (ATP). If the person is also
making a significant amount of ATP, it can result in superoxide, which
then binds to the nitric oxide to produce large amounts of
peroxynitrite, resulting in major problems with oxygen transport,
microcirculatory impairment and lack of tissue perfusion. To protect
the body from going down the death spiral, it stops making energy,
which results in significant reduction of superoxide and thus of
peroxynitrite.
Cheney discusses various methods of blocking peroxynitrite, including
pharmacological interventions (for example, the blocking of NMDA
reduces nitric oxide) and more basic methods such as increasing carbon
dioxide by re-breathing (carbon dioxide is a primary scavenger of
peroxynitrite). Uric acid is also a powerful scavenger of
peroxynitrite; Cheney has measured uric acid levels in CFIDS patients
and has found them to be amongst the lowest levels he has ever
measured in his entire medical career.
Cheney notes that the best endogenous scavenger of nitric oxide is
haemoglobin (a protein that transports oxygen from the lungs to the
tissues) but that when haemoglobin scavenges nitric oxide, the nitric
oxide bends the haemoglobin, causing the red blood cells to deform. Dr
Les Simpson in New Zealand found that the red blood cells of patients
with CFIDS were deformed and when deformed, they cannot get through
the capillary bed and so cause pain. An indication of such deformity
is a drop in the sedimentation rate (SED, or ESR) and Cheney has
observed that when measured in a laboratory, CFIDS patients'
sedimentation rate is the lowest he has ever recorded, which confirms
to Cheney that CFIDS patients have an induced haemoglobinopathy. He
believes that the CFIDS 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 CFIDS 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's bad enough when patients do not
perfuse their muscles and joints (because of poor microcirculation)
but it's 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 ME/ICD-CFS (an acquired haemoglobinopathy) and the third is
idiopathic cardiomyopathy.
Cheney observes that in order to improve cardiac output in CFIDS,
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. He has
found increasing the intake of potassium to be helpful (potassium
induces aldosterone, a hormone that significantly increases blood
volume), and that magnesium is beneficial as it is a vasodilator and
helps reduce the resistance the blood encounters.
Cheney is at pains to emphasise that none of these measures is a cure
---they are simply means to help patients disabled with CFIDS remain
as functional as possible.
In the UK, the question has to be asked: how can forced aerobic
exercise help such patients remain as functional as possible?
In the light of the Peckerman et al paper that was published in 2003,
are the psychiatrists and their peer reviewers at the MRC who approved
the PACE trial protocol still convinced that these trials (and the
exercise regimes to be meted out by the new Centres) pose no harm for
those with ME/ICD-CFS, or are they content to rely on the certainty
that they themselves can never be held accountable for any harm to any
patient because all participants must sign a compulsory waiver which
means that no participant can ever pursue any claim for medical
negligence or damages?
Another question needs to be asked and urgently answered: would it not
more effectively advance medical and scientific understanding of this
increasingly prevalent and devastating disorder if the MRC were at
last to let it be known that they would look favourably upon
applications for research funding submitted by those in disciplines
other than psychiatry?
Considering the rapidly increasing weight of available published data on organic pathology in ME/ICD-CFS (little of which is published in the UK medical literature), the MRC will inevitably have its hand forced eventually, as the time will come when such evidence can no longer continue to be ignored, but currently this seems to remain a forlorn hope.
Is this because the biomedical issues that have been shown by internationally respected researchers to underpin ME/ICD-CFS are deemed inconvenient in the UK as they do not accord with Government's preferred policy of off-loading as cheaply as possible the ever-increasing hordes of chronically sick who have no commercial value to the State but who cost it far too much money?
Surely this is a short-sighted policy, because it is well recognised that those who are correctly diagnosed and permitted to rest adequately in the initial stages are the ones who have hope of some recovery; moreover, if relevant research were to be instituted, it would lead to patients being investigated competently and treated correctly, thus offering the prospect of ME/ICD-CFS patients being able to return to an economically productive life.