Saturday, January 12, 2013

The muscle in ME: It isn't ALL deconditioning!

The muscle in ME: It isn't ALL deconditioning!
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
 
by Dr Vance A. Spence
 
Dr Vance Spence is the Chairman of MERGE, the national ME
research charity which commissions and funds biomedical
research into the illness
 
No wonder it is said that under-diagnosis kills more people
than any world war.
So many tests have no practical
application, no practical application at all.
 
Simoney Davies
 
Muscle pain and fatigue are extremely common complaints in
medical practice - so common that almost half of all patients
seeking medical care report them. It's hardly surprising then that
patients with these symptoms rarely have a definable muscle
disorder, i.e. one that can be diagnosed by neuro-physiological
testing, muscle biopsy or neuro-imaging.
 
In fact the term "muscle fatigue" is so vague that it is clinically
meaningless, and could reflect metabolic disease, a disorder of
the muscle fibres themselves, systemic effects of a viral illness,
depression, deconditioning or just aches and pains.
 
 
Had your muscles examined lately?
 
 It is in this light that we need to consider muscle symptoms in
ME In the historical literature, the hallmark of ME was marked
muscle fatigability often in response to minor degrees of
exercise. Muscle cramps, twitching and extreme muscle
tenderness were also common findings
.
 
"This was sometimes obvious as the patients winced even on
light palpitation of the affected muscle; but much more frequently
it took the form of minute foci [points] of muscle tenderness
which had to be carefully sought and for no ostensible reason
were generally found in the trapezii and gastrocnemii" [neck and
calf area].
 
The key words in Dr Ramsay's statement above are "which had
to be carefully sought"! Just how many ME patients have had
a proper clinical examination of their affected muscles? Very
few, judging by recent MERGE-funded clinical research at the
University of Dundee Medical School.
 
It is impossible nowadays to say how many ME patients there
are with the symptoms described by Dr Ramsay, given that ME
has been subsumed into the umbrella term chronic fatigue
syndrome which consists of vague, non- specific symptoms,
(principally persistent or relapsing fatigue), none of which are
specifically associated with muscle.
 
Imagine if oranges and lemons were classified as the same fruit,
how hard it would be to investigate characteristics such as
sourness in such a wide group. This is the problem of
researching muscle fatigue and pain in ME when all research is
in the context of CFS!
 
 
Why routine tests come back "normal"
 
So, given these complications, is there any evidence for
neuro-muscular dysfunction in CFS? Well, it depends what
you're looking for, and whether the tests have a practical
application specific to ME For example, most
neuro-physiological studies in the muscles of CFS patients -
including muscle biopsies - are for clinical/diagnostic purposes
and are used to exclude other muscle diseases. So, most
routine muscle investigations of patients with CFS are usually
"normal" in the sense that other recognised muscle disorders
cannot be found.
 
However, as outlined later, more sophisticated investigations
targeting areas of specific interest frequently show differences
between patients and well-matched control subjects.
 
In light of the oranges and lemons problem, it's not surprising
that one review of muscle pathology and biochemistry in CFS
has concluded that "overall, CFS is not a neuromuscular
disorder".
 
The same review continues, however: "There is probably a sub-
group in whom primary neuromuscular mechanisms for
abnormal fatigability do exist. At present we would consider
alternative neuromuscular diagnoses and/or mechanisms mainly
in subjects presenting with symptoms such as fatigue and
myalgia that are clearly exercise related, do not occur at rest,
and are not accompanied by any particular symptoms of mental
fatigability" .
 
Clearly, the subset of CFS patients fulfilling the classical
description of ME cannot just be ignored, and may indeed
require an alternative diagnosis to CFS.
 
 
On closer examination...
What kind of things have been shown to be abnormal in the
muscles of ME patients? Well, first, we have to recognise that
specific studies on these people - as distinct from those
diagnosed with CFS - are uncommon. In one study (ref. 5), the
Glasgow group showed that 40 out of 50 patients with post-viral
fatigue syndrome - an alternative name for ME - had
abnormalities of mitochondrial structure [mitochondrial cells make energy to power the body].
In a more recent study of
skeletal muscle tissue, there was evidence of impaired
mitochondrial structure and function.
 
 
One explanation for these findings is that they might be caused
by a persistent viral infection of muscle affecting the metabolic
machinery of the muscle cell without causing any obvious
microscopic tissue features
like inflammatory changes or cell
destruction ("necrosis").
 
Viruses have been isolated from the muscle of patients in
epidemic incidences of ME and about one-fifth of patients had
muscle samples that tested positive for viral particles but this
was raised to 50% when more sensitive polymerase chain
reaction (PCR) methods were applied . More recent evidence
has pointed to an association between abnormal exercise
lactate response and enterovirus sequences in the muscle of
approximately 20% of ME/CFS patients with no similar
abnormal findings in any of the matched control subjects . At
least one explanation has been provided favouring a persistent
infection with defective viral replication .
 
 
Drawing tentative conclusions
 
What can learn from these studies? We discover that a sub-set
of CFS patients - in the order of 20-30% - have abnormal
mitochondrial structure and enzyme function and that about the
same proportion - but not necessarily the same patients - have
evidence of viral activity in skeletal muscle tissue. Clearly, the
persistence of viral particles may well interfere with the muscles'
ability to carry out specialised functions. This is not a surprising
finding since fatigability and muscle pain (myalgia) are common
features of acute viral infections.
 
 
Furthermore, it's not surprising that the findings only apply to
around 30% of CFS patients, another indicator of the oranges
and lemons problem. This does raise important questions,
however, about the selection of patients for such studies and
whether they should be chosen on the basis of specific muscle
symptoms instead of relying on the vague criteria that
characterise CFS.
 
Researcher Dr Goran Jamal has written that despite an absence
of conspicuous muscle cell damage, a diagnosis of ME should
not be entertained without the most dominant and constant
feature of the illness: muscle fatigability and myalgia (ref 6).
 
 
Further abnormalities uncovered
 
One further recent discovery in the muscles of CFS patients
involves the mechanism of muscle contraction itself. The
suggestion is that something is wrong with the covering of the
muscle fibres which help transmit impulses, as well as some
aspects of calcium ion transport (important for the flow of nerve
impulses) in muscle biopsy samples taken from four
well-documented CFS patients . No such findings were apparent
in patients with fibromyalgia or in healthy control subjects.
 
Previous abnormalities of organic disturbance in the peripheral
part of the muscle motor unit (responsible for movement) were
reported by Dr Jamal in recordings of muscle jitter using single
fibre electromyography, and the findings were supported by
subtle changes in muscle tissue and ultra- structural damage to
the muscle fibre (ref 6).
 
These studies are very useful in that they provide evidence of
physical muscle disease in well- defined ME patients. They
should not be considered as diagnostic tests but as a starting
point for additional research work that might well be important in
terms of operational criteria for ME
 
 
It is also worth mentioning that blood markers of oxidative stress
might serve as an indirect and yet useful marker of an ongoing
problem with muscles in ME, as described in our previous
article in InterAction (May 2004). A clear relationship between
musculo-skeletal symptoms and blood markers of oxidative
stress in patients with CFS has recently been demonstrated .
 
Furthermore, samples of muscle from CFS patients have shown
significant increases in anti-oxidant defence enzymes. The
results also indicated, however, that oxidative damage to CFS
muscles arose not from a decline in the efficiency of the
anti-oxidant enzymes but from a disorder in the mitochondria,
the powerhouses of the body. It is important that funding be
obtained to continue this work, particularly as free radical
scavengers or agents to improve muscle function are potential
therapeutic targets for treatment.
 
 
Muscle pain and exercise
 
Should ME patients exercise? Much of the current thinking about CFS and ME is driven by models of deconditioning and the notion that a little regular exercise will be beneficial. That is true; some exercise is good for us all. But what if exercise results in a huge delivery of free radicals, not because of disuse
of muscle and deconditioning, but because there is something organically wrong with muscle metabolism? What value exercise in these circumstances?
 
These are crucial questions, and it is important to remember that
the current evidence for deconditioning is not based on scientific
investigations of muscle but on suppositions about patients with
"fatigue".
 
Again, ME is characterised by a delay in muscle recovery after
exercise (with pain and fatigue 24-48 hours after exertion), a
phenomenon which few have studied and which the
deconditioning hypothesis does not address. One study,
however, has confirmed patients' experience by demonstrating
that CFS patients fail to recover properly from a fatiguing
exercise protocol and that the failure was more pronounced after
24 hours .
 
 
Understanding muscle pain
 
Finally, it is worth asking how and why patients with ME feel
muscle pain and what changes in the muscle produce this pain.
 
These questions have already been asked and partly answered
by Professor Bengtsson in an editorial on fibromyalgia
syndrome (FMS) , who described how changes in the muscles
themselves, in the circulation and/or changes in muscle
activity/metabolism cause pain, fatigue and muscle weakness
.
 
There are similarities in the muscle symptoms experienced by
those with ME and FMS and it is worth speculating if the FMS
described by many Scandinavians is the same as historical and
more recent descriptions of ME
 
What is clear is that most muscle disorders are not painful.
However, the mechanisms of pain may not be the same in FMS
as ME and individual ME patients may have different causes
of their pain. Hypoxia (lack of oxygen) of muscle tissue will give
rise to pain and so post-exertional myalgia may well be driven by
an inadequate blood supply, a state of energy depletion during
exercise and the development of noxious free radicals.
 
This is a peripheral explanation for pain but it is important to
understand that chronic pain causes changes to the central
nervous system. So the pain experienced by ME patients is
likely to involve the brain and central nervous system as well as
the part of the body that feels sore!
 
The research evidence indicates that specific defects of muscle
functioning can be detected in many people with ME (i.e., in a
subset of people diagnosed with CFS).
 
Yes, exercise is good for everyone but not if it means that your muscles ache for days after it, so people with post-exertional
symptoms and muscle pain should exercise carefully; very
carefully.
 

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