Saturday, January 12, 2013

Biochemical Dysregulation of the 2-5A Synthetase/RNaseL Pathway

The evidence presented in this study more firmly establishes the dysregulation of the 2-5A synthetase/RNase L pathway in CFS.

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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
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
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

Chronic Fatigue Syndrome: How Does It Affect Sleep?

Patterns of Internet Usage and CFS

AK Knudsen, LV Lervik, SB Harvey, CMS Løvvik, AN Omenås, and A Mykletun
Comparison of chronic fatigue syndrome/myalgic encephalopathy with
other disorders: an observational study
J R Soc Med Sh Rep May 2012 3:32; doi:10.1258/shorts.2011.011167
The study is on internet usage

For this journal there is a 400-word, 5-reference limit to e-letters
or otherwise I would have written more.

Tom (@TomKindlon) i.e.


Dear AK Knudsen

Robert J Longworth, Retired

No affiliation

Dear AK Knudsen

I note that in the discussion section, 3rd paragraph, 9th line the
authors acknowledge that a previous study had shown that multiple
sclerosis had a higher online activity than me/cfs.

"The results from this study are in line with findings from Davison et
al.,20 who found CFS to have the second highest level of online
activity, after multiple sclerosis."

Why then did the authors design a study that did not include multiple
sclerosis as a comparison? Especially as the authors have concluded
that me/cfs has ten times the relative online activity of any other
disorder or condition.

Do the authors think that by not including multiple sclerosis as a
comparison to me/cfs, they were achieving best practise for a
scientific study? I note also that there is not mention of this matter
as being a weakness in their study.

Since the authors have acknowledged a possibility that online activity
for multiple sclerosis may be higher than for me/cfs, do the authors
think that the possible explanations for this high activity is the
same for both illnesses.

Do the authors consider a possible explanation for people with
multiple sclerosis having a high online activity, is due to being
isolated with a debilitating physical illness, loneliness and seeking
companionship. I note these possible explanations were not listed for
the high online activity of me/cfs people.

Robert Longworth

Conflict of Interest: None declared

Published 24 July 2012

RE: Comparison of chronic fatigue syndrome/myalgic encephalopathy with
other disorders: an observational study
Tom Kindlon
Irish ME/CFS Association

Knudsen and colleagues raise an interesting issue. However, I believe
they could have helped ensure better matching by using other groups of
patients with chronic illnesses such as multiple sclerosis which, as
the authors highlighted, had previously been found to have higher
online activity than Myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS). Perhaps in time the field will develop and
statistical tools like regression could help isolate which independent
variables predict online activity, and hence help isolate communities
with unusual patterns.

It would have been interesting if the authors had gathered qualitative
information on the topics discussed, to see if there were differences
not just in the quantity of activity but also in terms of the range of
topics discussed, and how they were discussed in different groups.
ME/CFS is often said to be a heterogeneous condition (1); similarly in
my experience, users of ME/CFS online forums are not all the same in
terms of their interests (what they like to discuss or read about).
This can be seen in the different types of groups that show up in a
search of, for example: there are chat groups;
groups interested in experimental therapies; groups interested in
activism of one sort or another; groups interested in discussing
research findings, etc.

The authors suggest that the high level of activity in ME/CFS could be
explained by action proneness (2). However that study was
retrospective and thus could be affected by recall bias. Research that
utilised an "action proneness" questionnaire, when individuals were
actually ill with ME/CFS, found lower levels compared to the general
population (1).

The paper also mentions the "boom-bust" theory with regard to activity
levels in ME/CFS. However, there is evidence that activity levels in
ME/CFS patients don't fluctuate any more than control groups (3,4).

We are told that "research on support group participation for CFS/ME
sufferers indicates that active members report greater symptom
severity and less improvement of the disorder than inactive members
(5)". However the study, which also involved fibromyalgia, found that
employment rates, an important measure of overall functioning was not
statistically different between the two groups.

If there are particular issues in ME/CFS that are driving patients to
internet forums, perhaps in time they will improve e.g. the
stigmatisation mentioned. Also, more effective therapies for ME/CFS
may become available - currently there are no FDA approved drugs for
the condition, which can lead patients to be interested in numerous
speculative therapies.

(1) Kindlon T. Reporting of Harms Associated with Graded Exercise
Therapy and Cognitive Behavioural Therapy in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME.
(last accessed: January 4, 2013)
(2) Van Houdenhove B, Onghena P, Neerinckx E, Hellin J. Does high
'action-proneness' make people more vulnerable to chronic fatigue
syndrome? A controlled psychometric study. J Psychosom Res. 1995
(3) Meeus M, van Eupen I, van Baarle E, et al. Symptom fluctuations
and daily physical activity in patients with chronic fatigue syndrome:
a case-control study. Arch Phys Med Rehabil. 2011 Nov;92(11):1820-6.
(4) van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW,
Bleijenberg G. Identifying physical activity patterns in chronic
fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000
Nov;49(5):373 -9.
(5) Friedberg F, Leung DW, Quick J. Do support groups help people with
chronic fatigue syndrome and fibromyalgia? A comparison of active and
inactive members. J Rheumatol 2005;32:2416-20

Conflict of Interest:
I am the Assistant Chairperson and Information Officer of the Irish
ME/CFS Association. All my work for the Association is unpaid.
Published 10 January 2013
* * *
The author makes a good point that those of us who are homebound and isolated are using the internet for companionship.  We're not being depressed and avoiding other people, we've found a way to bring other people to where we are.  I couldn't go out to meet people, so I made new friends online; people who don't judge me based on stereotypes. 
These new friends know, without long complicated explanations, what I'm dealing with and why I can't just pop out for a bottle of milk when I need it.  No criticism about laziness -- when I admit the only thing I got done all day was a load of laundry, I get cheers for having felt well enough to do the whole process in one day, not strip the bed on Monday, carry it to the laundry room on Tuesday, put it in the washer on Wednesday....  When you're as sick as we are, you need someone to cheer your smallest accomplishments, not some healthy person to scoff that she cleaned her whole house, did 14 loads of laundry and still had the energy to take an aerobics class and spend 3 hours at the mall.
Maybe the reason active members have greater symptom severity is the cause, not the result, of greater online activity.  We're too sick to work, so we have more time to participate in internet groups.  We have symptoms so bad that we're not able to live with them, so we have more reason to look for treatments.  Personally, I spent more time on CFS sites when I'm really sick, and less time on them when I'm functioning well enough to work, because work takes away from the time I can spend online.

An ME/CFS Celebration: Dr. Klimas and Nova Southeastern’s Coming Out Party

Thursday, January 10, 2013

Falling in Love at 49 | Midlife Crisis Queen: It's never too late

And besides being a shy, private person himself, Mike was also fearful of bringing another into his off and on struggle with chronic fatigue (CFS).
* * *
This is always a concern.  In addition to the usual pitfalls of dating, we have to find someone who can cope with the symptoms and flexibility.  My ex was not particularly good at flexible, and took it as a personal affront when I didn't feel up to doing something with him.  I wanted to do something with him, just not the physical activity he wanted to do that day; I would've been happy to curl up on the couch with a movie, or maybe even go out to a movie, but he couldn't flex that way.
There are other posts in this blog about dating, and links to dating websites that specialize in the disabled.  Do a search for them, because this is one of those days that I'm not up to much beyond getting food. 

Sunday, January 6, 2013

Ampligen Call to Action


This is it, folks. This letter shown below is the action that can cause the medical community, the government,the public, and big pharma to believe believing ME/CFS is real. We need to write letters to all those listedin the email below protesting the failure of the Food and Drug Administrationto approve the only drug for ME/CFS that has gone through numerous clinicaltrials – Ampligen.

On December 20th the FDA's Arthitis AdvisoryCommittee found the data supporting Ampligen not to be as convincing for"efficacy" as they would have liked, although the majority of the votingcommittee believed it to be safe. Theirturn down is not final, however. Higherlevel people in the FDA will have until February 2nd to make a finaldecision. Lyrica, for instance, wasinitially turned down for approval but was approved in the time between thefirst vote on it and its final decision date.

Here is what is at stake -- it's not just about Ampligen!

A drug, Ampligen, known to work for many ME/CFS patients, can get approved for us by the federal government (FDA). This will make the drug available nationwide at many locations, and likely to eligible for having insurance companies and Medicare pay for it. Hundreds of thousands of patients might well be improved somewhat or very greatly. Maybe you!

The medical community tends to believe in diseases if there are drugs approved for those diseases. It is a major reason why ME/CFS is so disrespected – "no drug, must not be real." The public will come to respect ME/CFS for the same reason.

The pharmaceutical companies will see that the size of the suffering patient population can be a moneymaker if they can develop other drugs for ME/CFS. If Ampligen is not approved, big pharma will lose interest in our disease for years, if not decades.

The National Institutes of Health (NIH), the Centers for Disease Control (CDC) and other funding arms of the federal government will be much more likely to give money to ME/CFS clinical trials since "it is a real disease," i.e., it has a drug already approved to treat it. Right now there are many doctors who would like to test medications and other treatments for ME/CFS who simply cannot get funding. $6 million for CFS in the NIH budget in 2011. $3 billion for HIV/AIDS. About the same number of patients!!

PLEASE WRITE to those peoplelisted in the sample email below. Sendthe same email, or write your own, telling your own story. Please do this quickly, as the FDA can make adecision anytime before February 2nd. They are not obligated to wait until then todecide. Please write daily – numbers ofletters matter!


To: Secretary KatherineSebelius
CommissionerMargaret Hamburg
DirectorJanet Woodcock
DeputyDirector Sandra Kweder

CC: SenatorRichard Blumenthal
SenatorRobert Casey
Senator KayHagen
CongressmanJoseph Pitts

Email addresses:



The FDA shouldapprove Ampligen by Feb 2, 2013. Patients and our physicians musthave the opportunity to access a treatment that has shown such promise forME/CFS patients. Failure to do so leavesus with no FDA-approved options to treat this disease.

The FDA has stated that ME/CFS is a serious and lifethreatening disease. Yet, withouttreatment, patients and their families are left to suffer. Many of us are bedbound or homebound. We are in constant pain and suffering,abandoned to bodies that torture us every day and demands that we parse out ouractivities like a single piece of bread that must last for a month. According to one retrospective study, patientsare more likely to die prematurely from cancer, heart failure or suicide. Thisis the long-term reality of living, untreated, with ME/CFS. Imagine living with an untreatable disease soterrible that you would choose suicide to escape from it.

Over 700 written and over 30 in-person patient testimonies,including that from the AAC patient representative, conveyed how profoundlythis devastating disease impacts our lives and the risk we are willing to takefor the opportunity to escape from this terrible physical burden and get backeven a piece of our lives.

For us, even small improvements have a very significantimpact on our quality of life. It isevident that Ampligen has provided benefit to patients, with the testimony anddata pointing to meaningful change in our ability to function and care forourselves.

The true nature of this disease and the plight of patients havebeen ignored for too long. Remember that the disease itself has a collateralimpact that creates its own serious risks for patients. Risk/benefit may be thecurrent standard, but there is a third factor – the risk of no approved treatment.
Patient testimony and patient and clinician experienceprovide evidence that this drug works in patients. A number of AAC membersagreed that Ampligen helps, and other members noted that they saw an indicationof effectiveness in patients. ApproveAmpligen and let patients and their doctors decide whether to take thisopportunity for patients to find some relief from the living death that istheir reality today.

The advisorycommittee voted that Ampligen's safety profile is adequate for approval. Approve Ampligen by Feb 2, 2013. Anything less is condemning one millionAmericans to years of continued suffering without any hope of relief.
Thank you.

Government lawyers say Harvey Whittemore's claims 'meritless'