Thursday, July 23, 2009

Documented Pathology that Contra-indicates Exercise

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Documented pathology seen in ME/CFS that contra-indicates the use of Graded
Exercise Therapy
 
 
Margaret Williams                 23rd July 2009
 
 
The evidence-base of pathology that has been demonstrated in ME/CFS appears
within a larger document that is already in the public domain, but is now
provided as a 9 page separate item for ease of access.
 
The UK ME/CFS community may not yet be fully aware of the content of Dr
Esther Crawley's presentation on 8th July 2009 to the Countess of Mar's
"Forward -ME" group meeting held at the House of Lords.  The Minutes of that
meeting and Dr Crawley's power-point presentation are accessible at
http://www.forward-me.org.uk/8th%20July%202009.htm
 
Of particular note are the following points made by Dr Crawley:
 
•         The CCRNC (CFS/ME Clinical and Research Network and Collaboration,
of which she is Chair) is a "multidisciplinary organisation which exists to
promote and support the delivery of evidenced based treatment for children,
young people and adults with CFS/ME throughout the UK" whose objective is
"To champion evidence-based approaches to the treatment of CFS/ME, such as
those provided in the NICE guidelines" and which will use "clinical
expertise to inform healthcare policy" and will "provide training for
clinicians and researchers from all disciplines involved in the diagnosis
and treatment of CFS/ME".
 
•         The CCRNC has an "Active training programme" and has "the ability
to provide national training programmes".
 
•         The CCRNC will "invite no more than four people drawn from
National UK CFS/ME organisations which explicitly support the aims and
constitution of the organisation to sit on the Executive committee as either
observers or members".
 
•         Its research strength is that it has the "Largest cohort in the
world".
 
•         Its strengths are "working together -- 600 clinicians and
researchers, MRC, NIHR (National Institute for Health Research), Welcome
(sic), patient and carer reps, charity membership".
 
 
It is particularly notable that the Minutes record that when asked by Dr
Charles Shepherd "whether, in the light of the widespread opposition to the
NICE Guidelines, charities that were opposed to them would be invited to
become members or associates of the CCRNC executive", Dr Crawley's response
was: "In order to join the collaborative, charities would be expected to
sign up to the evidence-based approach".
 
The only possible interpretation of this is that patients' charities are
welcome to participate provided that they accept the behavioural
modification interventions of CBT/GET recommended in the NICE Guideline (for
which Dr Crawley was a member of the Guideline Development Group).
 
This would seem to be something akin to medical totalitarianism, especially
given that Wessely School "evidence-base" upon which the NICE Guideline is
predicated has been so stringently criticised by international ME/CFS
experts. 
 
See, for example: http://www.meactionuk.org.uk/JR_Statements_-_extracts.htm  
 
It is worth recalling that at the Royal Society of Medicine meeting on
"Medicine and me: ME and CFS" held just three days later on 11th July 2009,
MRC Professor of Clinical Immunopharmacology Stephen Holgate said that at
the MRC, referees tend to reinforce the status quo and that he was not sure
if his wish for an MRC inter-disciplinary group involving immunologists,
neurologists and infectious diseases physicians would happen, which would
seem to indicate that the psychiatrists' stranglehold on MRC funding for
biomedical research into ME/CFS is set to continue.
 
The Forward-ME Minutes also record that Dr Crawley said: "the reputation the
CFS/ME charities had for infighting was not particularly helpful and
prevented research and clinical involvement".
 
Given that the "infighting" may have arisen because of the polarised views
about the nature of ME/CFS, with the Government-funded charities (Action for
ME and The Association of Young People with ME, to the latter of which Dr
Crawley is Medical Advisor) supporting the NICE Guideline that is
underpinned by flawed research, whilst other charities base their stance on
the international evidence that shows the NICE Guideline to be seriously
misinformed, it may be timely to look again at the following
"evidence-base".
 
Dr. Crawley stated that only those ME/CFS charities which agree to "sign up
to the evidence based approach" are to be permitted to join her
"collaborative". 
 
Given the volume of biomedical evidence that does not support Graded Exercise Therapy it would appear that in this instance signing up to an "evidence based approach" involves signing up to an approach that ignores most of the evidence.
 
Science is not furthered by a self-reinforcing "collaborative" determined to
exclude dissenting voices; rather, a vigorous and honest dialectic is
required. Medicine has no place for cabals and the lazy thinking they
foster.
 
The "Forward-ME" Minutes record that Lady Mar said she hoped that Dr Crawley
would "agree to continue to work with Forward-ME"; one can only wonder,
sadly, just how far backwards her "Forward-ME" initiative will carry the UK
ME/CFS community.
 
 
Evidence-based research showing pathology that contra-indicates the use of
graded exercise in ME/CFS
 
There is an extensive literature from 1956 to date on the significant
pathology that has been repeatedly demonstrated in ME/CFS, but not in
"CFS/ME" or "chronic fatigue"; this can be accessed on the ME Research UK
website at http://www.meresearch.org.uk/information/researchdbase/index.html
and also at http://www.meactionuk.org.uk/Organic_evidence_for_Gibson.htm  .
 
According to Professor Nancy Klimas, ME/CFS can be as severe as congestive
heart failure and the most important symptom of all is post-exertional
relapse (presentation at the ME Research UK International Conference held in
Cambridge in May 2008).
 
Unique vascular abnormalities have been demonstrated in ME/CFS, with markers
of oxidative stress. Oxidative stress is caused by highly reactive molecules
known as free radicals circulating in the bloodstream of people with ME/CFS
and results in cell injury. Oxidative stress levels are raised in ME/CFS and
are associated with clinical symptoms.
(Kennedy G, Spence VA, McLaren M,
Hill A, Underwood C, Belch JJF. Free Radical Bio Med. 2005;39:584-589).
 
Exercising muscle is a prime contender for excessive free radical generation
(Niess AM, Simon P. Front Biosci. 2007 Sep 1;12:4826-38).
 
Research has shown that many patients with ME/CFS may have an inflammatory
condition and be in a 'pro-oxidant' state
(Klimas NG, Koneru AO.  Curr
Rheumatol Rep. 2007;9(6):482-7).
 
In 1983, UK researchers documented evidence of a consistent pattern of
complexity, including  "malaise, exhaustion on physical or mental effort,
chest pain, palpitations, tachycardia, polyarthralgia, muscle pains, back
pain, true vertigo, dizziness, tinnitus, nausea, diarrhoea, abdominal
cramps, epigastric pain, headaches, paraesthesiae and dysuria"
  (Keighley
and Bell, JRCP: 1983:339-341).
 
In 1984, Arnold et al demonstrated excessive intracellular acidosis of
skeletal muscle on exercise in ME/CFS patients, with a significant
abnormality in oxidative muscle metabolism and a resultant acceleration in
glycolysis
(Proceedings of the Third Annual Meeting of the Society for
Magnetic Resonance in Medicine, New York: 1984: 12-13).
 
In 1985, UK researchers demonstrated muscle abnormalities in ME/CFS
patients: "The post-viral fatigue syndrome, also known as ME, has been
recognised recently as a distinct neurological entity with increasing
evidence of the organic nature of the disease. The most important findings
were type II fibre predominance, subtle and scattered fibre necrosis and
bizarre tubular structures and mitochondrial abnormalities. About 75% of the
patients had definitely abnormal single fibre electromyography results"
(Goran A Jamal   Stig Hansen   JNNP 1985:48:691-694).
 
In 1987, Archer demonstrated that: "Relapses are precipitated by undue
physical or mental stress. However compelling the evidence for an hysterical
basis may be, there is further, equally compelling, evidence of organic
disease. Some patients do have frank neurological signs. Muscle biopsies
showed necrosis and type II fibre predominance"
(JRCGP: 1987:37:212-216).
 
It was documented as long ago as 1988 that there was "general agreement that
(ME's) distinguishing characteristic is severe muscle fatigability, 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
" (Crit Rev
Neurobiol: 1988:4:2:157-178).
 
In 1988, UK researchers Archard and Bowles et al published the results of
their research into muscle abnormalities in ME/CFS: "These data show that
enterovirus RNA is present in skeletal muscle of some patients with
postviral fatigue syndrome up to 20 years after onset of disease and suggest
that persistent viral infection has an aetiological role. These results
provide further evidence that Coxsackie B virus plays a major role in ME,
either directly or by triggering immunological responses which result in
abnormal muscle metabolism" (
JRSM 1988:81:325-331).
 
Also in 1988, Teahon et al published a study of skeletal muscle function in
ME/CFS; it showed significantly lower levels of intracellular RNA,
suggesting that ME/CFS patients have an impaired capacity to synthesise
muscle protein, a finding which cannot be explained by disuse
(Clinical
Science 1988: 75: Suppl 18:45).
 
In 1989, Professor Tim Peters spoke at a meeting of microbiologists held at
the University of Cambridge: "Other muscle abnormalities have been reported,
with decreased levels inside the cell of a key enzyme called succinate
dehydrogenase, which plays an important role in energy production inside the
mitochondria (the power house of the cell)".  A report of this conference
was published in the ME Association Newsletter, Autumn 1989, page 16.
 
In 1990, a UK researcher pointed out the folly of CBT/GET: "It has been
suggested that a new approach to the treatment of patients with postviral
fatigue syndrome would be the adoption of a cognitive behavioural model"
(Wessely S, David A et al. JRCGP 1989:39:26-29).  Those who are chronically
ill have recognised the folly of the approach and, far from being
maladaptive, their behaviour shows that they have insight into their
illness"
  ( D O Ho-Yen    JRCGP 1990:40:37-39).
Also in 1990, the BMJ published an important study: "Patients with the
chronic fatigue syndrome have reduced aerobic work capacity compared with
normal subjects. We found that patients with the chronic fatigue syndrome
have a lower exercise tolerance than normal subjects. Previous studies have
shown biochemical and structural abnormalities of muscle in patients with
the chronic fatigue syndrome" (Aerobic work capacity in patients with
chronic fatigue syndrome.
   MS Riley DR McClusky et al 
BMJ:1990:301:953-956).
 
In 1991, evidence of muscle damage in ME/CFS was demonstrated by Professor
Wilhelmina Behan from Glasgow: "The pleomorphism of the mitochondria in the
patients' muscle biopsies was in clear contrast to the findings in the
normal control biopsies. Diffuse or focal atrophy of type II fibres has been
reported, and this does indicate muscle damage and not just muscle disuse". 
This study was done on a fairly homogeneous population and 80% of the
biopsies showed structural damage to the mitochondria
  (Acta Neuropathol
1991:83:61-65).
 
In 1992, US researchers (including Robert Gallo, the co-discoverer of the
HIV virus) found that "57% of patients were bed-ridden, shut in or unable to
work. Immunologic (lymphocyte phenotying) studies revealed a significantly
increased CD4 / CD8 ratio. Magnetic resonance scans of the brain showed
punctate, subcortical areas of high signal intensity consistent with oedema
or demyelination in 78% of patients. Neurologic symptoms, MRI findings, and
lymphocyte phenotyping studies suggest that the patients may have been
experiencing a chronic, immunologically-mediated inflammatory process of the
central nervous system" (A chronic illness characterized by fatigue,
neurologic and immunologic disorders, and active human herpes Type 6
infection.  
  Dedra Buchwald, Paul Cheney, Robert Gallo, Anthony L Komaroff
et al   Ann Intern Med 1992:116:2:103-113).
 
Also in 1992, the US Department of Health and Human Services produced a
pamphlet on ME/CFS for the guidance of physicians (NIH Publication No.
92-484) which stated: "ME/CFS symptoms overlap with those of many
well-recognised illnesses, for example, lupus erythematosus (SLE) and
multiple sclerosis. Psychiatric evaluations fail to identify any psychiatric
disorders.
Many people with ME/CFS have neurologic symptoms, including
parasthesias, dysequilibrium and visual blurring.  A few patients have more
dramatic neurologic events such as seizures, periods of severe visual
impairment, and periods of paresis. Evidence suggests that several latent
viruses may be actively replicating more often in (ME)CFS patients that in
healthy control subjects. Most investigators believe that reactivation of
these viruses is probably secondary to some immunologic challenge. It is
important to avoid situations that are physically stressful".
 
On 18th February 1993, Professor Paul Cheney testified before the US FDA
Scientific Advisory Committee as follows: "I have evaluated over 2,500
cases. At best, it is a prolonged post-viral syndrome with slow recovery. At
worst, it is a nightmare of increasing disability with both physical and
neurocognitive components. The worst cases have both an MS-like and an
AIDS-like clinical appearance.
We have lost five cases in the last six
months.  The most difficult thing to treat is the severe pain.  Half have
abnormal MRI scans. 80% have abnormal SPECT scans. 95% have abnormal
cognitive-evoked EEG brain maps. Most have abnormal neurological
examination. 40% have impaired cutaneous skin test responses to multiple
antigens.  Most have evidence of T-cell activation.   80% have evidence of
an up-regulated 2-5A antiviral pathway.
 80% of cases are unable to work or
attend school.  We admit regularly to hospital with an inability to care for
self". 
 
Also in 1993, Professor Anthony Komaroff from Harvard published his
"Clinical presentation of chronic fatigue syndrome" in which he stated: 
"ME/CFS can last for years and is associated with marked impairment. (It) is
a terribly destructive illness. The tenacity and ferocity of the fatigue can
be extraordinary. As for the symptoms that accompany the fatigue, it is
striking that these symptoms are experienced not just occasionally but are
present virtually all the time. In our experience, 80% of patients with
ME/CFS have an exceptional post-exertional malaise. (Physical examination
findings) include abnormal Romberg test (and) hepatomegaly (and)
splenomegaly. Anyone who has cared for patients with ME/CFS will recognize
that (the) description of the patient with lupus eloquently describes many
patients with ME/CFS as well"
(In: Chronic Fatigue Syndrome.  John Wiley &
Sons, Chichester. Ciba Foundation Symposium 173:43-61).
 
In 1993, UK researchers Barnes et al demonstrated that there is a
significant abnormality in oxidative muscle metabolism with a resultant
acceleration in glycolysis in ME/CFS patients
  [cf. the work of Arnold in
1984 above] (JNNP:1993:56:679-683).
 
In 1995, UK researchers Lane and Archard published the article "Exercise
response and psychiatric disorder in chronic fatigue syndrome", which
stated: "In previous studies patients with ME/CFS showed exercise
intolerance in incremental exercise tests.  We examined venous blood lactate
responses to exercise at a work rate below the anaerobic threshold in
relation to psychiatric disorder. Our results suggest that some patients
with ME/CFS have impaired muscle metabolism that is not readily explained by
physical inactivity or psychiatric disorder"
(BMJ 1995:311:544-545).
 
That same year, UK researchers Geoffrey Clements et al reported that:
"Enteroviral sequences were found in significantly more ME/CFS patients than
in the two comparison groups. The presence of the enteroviral sequences in a
significant number of patients points to some role in ME/CFS.  A variety of
immunological disturbances have been reported for ME/CFS patients which may
relate in some way to the enteroviral persistence. This study provides
evidence for the involvement of enteroviruses in just under half of the
patients presenting with ME/CFS and it confirms and extends previous studies
using muscle biopsies. We provide evidence for the presence of viral
sequences in serum in over 40% of ME/CFS patients
" (J Med Virol
1995:45:156-161).
 
In 1997, Charles Lapp, Professor of Community Medicine at Duke University,
Charlotte, North Carolina, found that a trial allowing ME/CFS patients to
reach their maximum oxygen consumption within 8-10 minutes of exercise
caused 74% to experience a worsening of fatigue and that none improved.  The
average relapse lasted 8.82 days.  Lapp concluded: "These findings suggest
that, pushed to maximal exertion, patients with ME/CFS may relapse"
(Am J
Med 1997:103:83-84).
 
In 1998, a study of autonomic function by Rowe and Calkins found that
"Virtually all ME/CFS patients (regardless of their haemodynamic response)
have their symptoms provoked by standing upright"
(Am J Med 1998:105:
(3A):15S – 21S).
 
Also in 1998, US researchers presented key evidence: "The results showed
that in ME/CFS patients, a lower stroke volume was highly predictive of
illness severity: across three different postures, the most severely
affected patients were found to have a lower stroke volume and cardiac
output compared with those with more moderate illness.
These findings
suggest a low flow circulatory rate in the most severe cases of ME/CFS; this
may indicate a defect in the higher cortical modulation of cardiovascular
autonomic control. In the most severely affected, situations may arise where
a demand for blood flow to the brain may exceed the supply, with a
possibility of ischaemia and a decrement of function"
  (Arnold Peckerman  
Benjamin Natelson et al.  Presented at the Fourth International AACFS
Research & Clinical Conference on ME/CFS, Mass. USA).
 
In 1998, Racciatti et al found that "(ME)CFS is a severely disabling
illness. Regional brain perfusion impairment (mainly hypoperfusion) was
found in 83.9% of (ME)CFS patients. This study confirmed previous reports of
brain perfusion impairment in (ME)CFS, providing objective evidence of
central nervous system dysfunction".
  ("Brain SPET in Chronic Fatigue
Syndrome": Fourth AACFS International Research & Clinical Conference, Mass:
USA).
 
That same year, UK researchers Russell Lane and Leonard Archard published
their findings of muscle abnormalities in response to exercise in ME/CFS
patients: "The object of this study was to examine the proportions of types
I and II muscle fibres and the degree of muscle fibre atrophy and
hypertrophy in patients with ME/CFS in relation to lactate responses to
exercise, and to determine to what extent any abnormalities found might be
due to inactivity. Muscle fibre histometry in patients with ME/CFS did not
show changes expected as a result of inactivity
. The authors note that one
of these patients had an inflammatory infiltrate, and it would seem that
inflammation and class I MHC expression may occur in biopsies from patients
with ME/CFS. The authors note that this is of some interest, as they have
argued previously that some forms of ME/CFS may follow a previous
virally-mediated inflammatory myopathy". In general, following exercise,
patients with ME/CFS showed more type I muscle fibre predominance and
infrequent muscle fibre atrophy, unlike that which would be expected in
healthy sedentary people.
(JNNP 1998:64:362-367).
 
In 1999, Paul et al provided irrefutable evidence of delayed muscle recovery
after exercise. That paper states: "The use of 31 P-nuclear magnetic
resonance (31 P-NMR) has now provided positive evidence of defective
oxidative capacity in ME/CFS. Patients with ME/CFS reach exhaustion more
rapidly than normal subjects, in keeping with an abnormality in oxidative
metabolism and a resultant acceleration of glycolysis in the working
skeletal muscles. When the rate of resynthesis of phosphocreatinine (PCr)
following exercise is measured, this abnormality is confirmed. (This)
provides a conclusive demonstration that recovery is significantly delayed
in patients with ME/CFS. The results demonstrate that patients with ME/CFS
fail to recover properly from fatiguing exercise and that this failure is
more pronounced 24 hours after exercise"
(European Journal of Neurology
1999:6:63-69).
 
In 2000, an important Belgian / Australian collaborative study entitled
"Exercise Capacity in Chronic Fatigue Syndrome" was unequivocal: "Comparing
the exercise capacity in our patients with data from other studies shows a
functionality similar to that of individuals with chronic heart failure,
patients with chronic obstructive pulmonary disease, and those with skeletal
muscle disorder". Specific findings included (i) the resting heart rate of
patients was higher than controls but patients' maximal heart rate at
exhaustion was lower than controls  (ii) the maximal workload achieved by
patients was almost half that achieved by controls  (iii) the maximal oxygen
uptake was almost half that achieved by controls.  This would affect
patients' physical abilities, leading the authors to comment: "This study
clearly shows that patients with ME/CFS are limited in their capabilities".
Taken together, these findings "suggest that alteration in cardiac function
is a primary factor associated with the reduction in exercise capacity in
ME/CFS"
(P De Becker et al. Arch Intern Med 2000:160:3270-3277).
 
In 2001 an Australian study by Sargent, Scroop, Burnett et al from the
Adelaide CFS Research Unit found that ME/CFS patients are not de-conditioned
and that "There is no physiological basis for recommending graded exercise programmes" (The Alison Hunter Memorial Foundation ME/CFS Clinical and
Scientific Meeting, Sydney, Australia, December 2001).
 
This was later published (Med. Sci. Sports Exerc: 2002:34:1:51-56) and the
authors stated: "The fatigue is often present at rest and exacerbated by the
simplest of physical tasks. The purpose of the present study was to employ
'gold standard' maximal exercise testing methodology. Exercise performance is well recognised to be impaired in ME/CFS patients, with a reduced exercise time to exhaustion being a common finding. The present findings indicate that physical deconditioning (is not) a critical factor in the fatigue that (patients) experience.  Although the recommendation or imposition of exercise-training programmes may have benefit in terms of social interaction, such programmes could well be based on a false premise if the intention is to improve well-being by correcting the effects of deconditioning".
 
In 2003, Professor Ben Natelson from the US found that "The patients with ME/CFS (indicated) profound physical impairment.  These scores tended to be
below the published norm for patients with cancer, congestive heart failure and myocardial infarction"
(J Nerv Ment Dis 2003:191:324-331).
 
Also in 2003, Peckerman and Natelson et al from the US were specific about
circulatory problems in ME/CFS: "Findings indicative of a problem with
circulation have been reported in patients with ME/CFS. (Our) results
provide evidence of reduced cardiac output in severe ME/CFS. They suggest
that in some patients, blood pressure is maintained at the cost of
restricted flow, possibly resulting in a low circulatory state. Thus there
may be periods in daily activities when demands for blood flow are not
adequately met, compromising metabolic processes in at least some vascular
compartments. Several deficiencies capable of affecting cardiac output have
been reported in ME/CFS, including lower blood volume, impaired venous
regulation, and changes in autonomic, endocrine and cardiac function.
The
abnormalities causing a reduction in cardiac output in ME/CFS thus may be
dispersed over multiple systems. (Further research) should be directed at
conditions that may not be overtly expressed in symptoms of ME/CFS, such as
under-perfusion in the kidneys and the gut, as the organs in which the
initial conservation of cardiac output takes place. The patients with severe
ME/CFS had significantly lower stroke volume and cardiac output than the
controls and less ill patients. In summary, this study provides indication
of reduced cardiac output in some patients with ME/CFS
" (Am J Med Sci
2003:326:2:55-60).
 
In 2003, Byron Hyde, medical adviser on ME/CFS to the Canadian Government,
pointed out that "ME in adults is associated with measurable changes in the
central nervous system and autonomic function and injury to the
cardiovascular, endocrine and other organs and systems.
The patient with the
diagnosis of ME/CFS is chronically and potentially seriously ill. These
ME/CFS patients require a total investigation and essentially a total body
mapping to understand the pathophysiology of their illness and to discover
what other physicians may have missed.  A patient with ME is a patient whose
primary disease is central nervous system change, and this is measurable. 
The belief that ME/CFS is a psychological illness is the error of our
time".   (The Complexities of Diagnosis.  Byron Hyde.   In: Handbook of
Chronic Fatigue Syndrome   Leonard A Jason et al.   John Wiley & Sons, Inc.
2003).
 
In 2003 an important UK study of skeletal muscle tissue by neurologist
Russell Lane et al provided evidence of impaired mitochondrial structure and
function
in ME/CFS patients, once again demolishing the "de-conditioning"
theory (JNNP: 2003:74:1382-1386).

 
In the Summer of 2004, Professors Christopher Snell and Mark VanNess from
the University of the Pacific (specialists in sports medicine and muscle
function who have been involved in ME/CFS research since 1998) published an
article in The CFIDS Chronicle in which they wrote: "Healthcare
professionals often recommend aerobic exercise as a cure-all for the
symptoms of ME/CFS without fully understanding the consequences (and) the
results can be devastating (and can lead to) symptom exacerbation,
post-exertional malaise and even collapse. It is obvious that persons with
ME/CFS do not recover well from aerobic activity.  This may be because, for
them, the activity is not aerobic.  The aerobic system depends on a constant
supply of oxygen being delivered to active muscles.  There is evidence that
this process may be impaired in ME/CFS. In the absence of an adequate supply
of oxygen, energy production shifts to anaerobic (without oxygen) process,
leading to oxygen debt.  Oxygen debt equals fatigue and before normalcy can
return (that debt) must be repaid. Interest rates on the (oxygen debt) may
be significantly high.
Exercise therapy for ME/CFS will not work because one
size does not fit all".
 
In October 2004, at the 7th AACFS International Conference held in Madison,
Wisconsin, Susan Levine from Columbia presented evidence of an analysis of
metabolic features using MRSI (magnetic resonance spectroscopy imaging)
which showed elevated lactate levels in ME/CFS patients, suggesting
mitochondrial metabolic dysfunction similar to mitochondrial
encephalomyopathy. Elevation of thalamic choline was also demonstrated,
suggesting the presence of neuronal damage.
 
At the same International Conference, Spanish researchers (Garcia-Quintana)
presented their work on aerobic exercise, providing evidence of low maximal
oxygen uptake in ME/CFS patients.  This confirmed previous studies showing
that patients with ME/CFS have a markedly reduced aerobic work capacity on
bicycle ergometry.
 
At this Conference, findings were presented by a Belgian team (Nijs) which
provided evidence of underlying lung damage through intracellular immune
dysregulation, with impairment of cardiopulmonary function – elevated
elastase levels could damage lung tissue and impair oxygen diffusion across
the alveoli in the lungs, potentially explaining decreased oxygen delivery
to tissues that is seen in ME/CFS.
  (This presentation was singled out as
being outstanding).
 
The "Exercise Workshop" at this same conference highlighted the
understanding that people with ME/CFS suffer exercise intolerance and
post-exertional malaise unless they stay within prescribed limits, the limit
suggested being the anaerobic threshold (AT -- this is the time during
exertion that the heart and lungs can no longer provide adequate oxygen to
muscles, and muscle metabolism changes from aerobic to anaerobic; it is well
known that this change occurs unusually early in people with ME/CFS). If the
anaerobic threshold is determined to occur at 4.5 minutes, then the patient
is advised to exert no more than 4 to 4.5 minutes before stopping to rest.
 
(For conference reports, see
http://www.drlapp.net/AACFS%20Meeting%20Summary.htm  by Professor Charles
Lapp from the US and Co-Cure NOT, RES: 2nd November 2004 by Dr Rosamund
Vallings from New Zealand).
 
In 2005, Black and McCully published their results of an exercise study in
patients with ME/CFS: "This analysis suggests that ME/CFS patients may
develop exercise intolerance as demonstrated by reduced total activity after
4 – 10 days.  The inability to sustain target levels, associated with
pronounced worsening of symptomatology, suggests the subjects with ME/CFS
had reached their activity limit
"  (Dyn Med 2005: Oct 24: 4 (1): 10).
 
Black and McCully's results concur with those of Bazelmans et al that were
published in the same year.  That study examined the effects of exercise on
symptoms and activity in ME/CFS: "For ME/CFS patients, daily observed
fatigue was increased up to two days after the exercise test.  For controls,
fatigue returned to baseline after two hours.  Fatigue in ME/CFS patients
increased after exercise"
(J Psychosom Res 2005:59:4:201-208).
 
Also in 2005, Jammes et al assessed increased oxidative stress and altered
muscle excitability in response to incremental exercise in ME/CFS patients:
"The data reported here were taken from well-rested subjects and research
has demonstrated that incremental exercise challenge potentiates a prolonged
and accentuated oxidant stress that might well account for post-exercise
symptoms in ME/CFS"
(J Intern Med 2005: 257 (3):299-310).
 
In 2006, Belgian researchers Nijs and De Meirleir reported on the observed
associations between musculoskeletal pain severity and disability, noting
that pain was as important as fatigue to ME/CFS patients: "A few years ago,
little was known about the nature of chronic musculoskeletal pain in
ME/CFS.  Research data gathered around the world enables clinicians to
understand, at least in part, musculoskeletal pain in ME/CFS patients. Fear
of movement (kinesiophobia) is not related to exercise performance in ME/CFS
patients.  From a pathophysiologic perspective, the evidence of a high
prevalence of opportunistic infections is consistent with the numerous
reports of deregulated and suppressed immune functioning in ME/CFS
patients.  Infection triggers the release of the pro-inflammatory cytokine
interleukin-1e which is known to play a major role in inducing
cyclooxygenase-2 (COX-2) and prostaglandin E2 expression in the central
nervous system. Upregulation of COX-2 and prostaglandin E2 sensitises
peripheral nerve terminals. Even peripheral infections activate spinal cord
glia (both microglia and astrocytes), which in turn enhance the pain
response by releasing nitric oxide (NO) and pro-inflammatory cytokines. 
These communication pathways can explain the wide variety of physiological
symptoms seen in ME/CFS. Experimental evidence has shown that ME/CFS
patients respond to incremental exercise with a lengthened and accentuated
oxidative stress response, explaining muscle pain and post-exertional
malaise as typically seen in ME/CFS.
  In many of the published studies,
graded exercise therapy has been adopted as a component of the CBT programme
(i.e. graded exercise was used as a way to diminish avoidance behaviour
towards physical activity).  Unfortunately, the studies examining the
effectiveness of GET/CBT in ME/CFS did not use musculoskeletal pain as an
outcome measure (and) none of the studies applied the current diagnostic
criteria for ME/CFS.  From a large treatment audit amongst British ME/CFS
patients, it was concluded that approximately 50% stated that GET worsened
their condition.  Finally, graded exercise therapy does not comply with our
current understanding of ME/CFS exercise physiology.  Evidence is now
available showing increased oxidative stress in response to (sub)maximal
exercise and subsequent increased fatigue and post-exertional malaise
(Manual Therapy 2006: Aug. 11(3):187-189).
 
In 2007 a study by Lerner et al found that "A progressive cardiomyopathy
caused by incomplete virus multiplication in ME/CFS patients is present"
 
(In Vivo 2004:18:4:417-424).
 
In 2007, collaborating researchers in Japan and America noted that people
with ME/CFS reported substantial symptom worsening after exercise, symptoms
being most severe on the fifth day. There was no cognitive or psychological
benefit to the exercise, and patients suffered physical decline
(Yoshiuchi
K, Cook DB, Natelson BH et al.  Physiol Behav  July 24, 2007).
 
In 2008, a collaborative study involving researchers from Belgium, the UK
and Australia (published by J Nijs, L Paul and K Wallman as a Special Report
in J Rehabil Med 2008:40:241-247) examined the controversy about exercise
for patients with ME/CFS.  Although published after the production of the
NICE Guideline, the paper contains relevant references showing adverse
effects of GET
that were published before the Guideline (and so were
available to the GDG):
 
"ME/CFS describes a disorder of chronic debilitating fatigue that cannot be
explained by any known medical or psychological condition. The Cochrane
Collaboration advises practitioners to implement graded exercise therapy for
patients with ME/CFS, using cognitive behavioural principles. CBT represents
a psychological and physical intervention approach aimed at assisting
individuals in re-evaluating concepts related to their illness and in
adopting thoughts and behaviours designed to promote recovery (the reference
for this statement is Chalder, Deale and Wessely et al. Am J Med
1995:98:419-420). This approach to GET advises patients to continue
exercising at the same level even when they develop symptoms in response to
exercise (two references are provided for this statement, one being Fulcher
KY and White PD, BMJ 1997:314:1647-1652 – this being one of the RCTs based
on the Oxford criteria that the Guideline Development Group relied upon for
its recommendation of GET.  The other reference was Clark LV and White PD (J
Mental Health 2005: 14: 237-252), in which Clark and White state that
patients with ME/CFS are de-conditioned, and argue that: "Patient education
is necessary to inform patients of the positive benefit / risk ratio in
order to improve acceptance and adherence").  Nijs et al continue:
"Conversely, there is evidence of immune dysfunction in ME/CFS, and research
shows further deregulation of the immune system in response to too-vigorous
exercise, leading to an increase in fatigue and post-exertional malaise. It
has been shown that even a 30% increase in activity frequently triggers a
relapse
(ref: Black CD, O'Connor, McCully K. Dynamic Medicine 2005:4:3). The
severe exacerbation of symptoms following exercise, as seen in patients with
ME/CFS, is not present in other disorders where fatigue is a predominant
symptom. This post-exertional malaise is a primary characteristic evident in
up to 95% of people with ME/CFS. It is possible that exercise at ANY
intensity that exceeds an ME/CFS patient's physical capabilities may result
in the worsening of symptoms. Early approaches to GET advised patients to
continue exercising at the same level when they developed symptoms in
response to the exercise.  This led to exacerbation of symptoms and adverse
feedback from patient and patient charities".

 
 
The understanding of ME/CFS cannot be furthered by the continued ignoring of
this evidence-base.
 
 
 
 
 

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