Mouse Wars

By Rick Jelliffe
October 16, 2010 | Comments: 4

Readers may be interested in an update on my blog 10 months ago (2009) XMRV - the third infectious human retrovirus. After the initial study finding high occurrence XMRV came four other independent studies which found absolutely no XMRV.

Updated: see Mouse hanging by thread

In October 2010, the US NIH held a Workshop on XMRV with many new studies presented from different sources. (abstracts here PDF) Dr Paul Cheney's comment on the workshop was that "The bio-political undertones were also intense" The results are very striking.

  • Four new studies found high signs of the XMRV virus in CFS patient's blood. Results were between 60% to 80% of current sufferers, based on fairly strict criteria.
  • Two new studies found no signs of the XMRV virus in CFS patient's blood. (One study that found no signs of XMRV in its own samples nonetheless detected them in samples from the original US study.)
  • One study found signs of the mouse retrovirus, but its authors were investigating whether it had been contaminated (by mice?)

So the original study's results have been replicated independently, several times. But so has the counter study. Now the scientists have to figure out why. Is it the collection methodology? Are some tests ineffective?

One source of variation is how the cohorts were selected. The studies that were based on patient samples derived from particular medical practices specializing in severe CFS had the higher results.

Does it float?

You would expect a mixed bag of results when apples are being compared with oranges.

In the late 1950s, UK doctors described Myalgic Encephalomyelitis with quite limited definition, such as that of Ramsay. The more modern Nightingale definition for ME requires an injury to the nervous system, and excludes pyschiatric definitions ("psychiatric diagnoses cannot be subjected to scientific examination").

The name post-viral syndrome has also been used, for example following glandular fever or Ross River fever, and there are a variety of overlapping or similar syndromes such as post-polio syndrome and Gulf War syndrome.

In the 1990s, there was a kind of re-branding of ME, under the name Chronic Fatigue Syndrome, with a much broader definition. The 1994 CDC (Fukuda) definition used in the US is somewhat vague or broad and concentrates on presences of fatigue. Most significantly, the detection of any other known medical conditions (whose manifestation includes fatigue) precludes a diagnosis of CFS.

The CDC definition is so broad that it can allow misdiagnosis of major depressive disorder.

And, indeed, there has been severe criticism in the UK of leading psychiatrists who, it seems, hold that CFS is to some extent caused by maladaptive coping strategies and recommend Cognitive Behavioral Therapy. (The use of CBT is controversial.) In the Oxford definitions used in the UK are even broader than the the CDC, and emphasize general fatigue.

Finally, a counter-response has been the Canadian Consensus definition which is much more specific, and emphasizes post-extertional fatigue. For a good 2004 version, see these South Australian Management Guidelines.

The media lumps all the studies together as concerning CFS, yet, it would seem reasonable that if there are a variety of definitions ranging from ones that are very strict in their requirements for measurable non-psychiatric symptoms, to those that may include psychiatric symptoms, to those which tend to exclude non-psychiatric conditions, that we would get a different selections of cohorts and of results.

Indeed, as a layman I find it a little difficult to see why a scientist using the CDC (Fukuda) or Oxford definitions alone to select study donors would not be shooting themselves in the foot. It might be useful for XMRV researchers to concentrate their studies to patients who meet both the Canadian and CDC definitions only, as well as for example being incapable of fulltime work.

[Update: I hadn't seen this when writing, but two days before I posted came this story CFS Panel Wants Name Change for Disorder.]

Update: "Empirical" CFS

I found a quite telling paper in the peer-reviewed Bulletin of the IACFS/ME (Northern) Summer 2010 edition by Sampson Close analysis of a large published cohort trial into fatigue syndromes and mood disorders that occur after documented viral infection. This article really spells out some of the issues I've outlined, and is based on a paper which compared several definitions of CFS, including a one that excludes most psychiatric conditions "Empirical" CFS.

From the conclusions section:

Firstly, close analysis of the data has shown that following viral infection, the strongest predictor of going on to develop a non-psychiatrically defined Fatigue Syndrome (Empirical), even 6 months later, is documented clinical evidence of specific viral infection (infectious mononucleosis) not previous psychiatric morbidity Significantly, in these patients, amount of bed rest at onset of infection is not predictive of having a fatigue syndrome 6 months later. This strongly argues that in such individuals exists a CFS/ME which has nothing to do with over-resting/deconditioning and has everything to do with some as yet undetermined physical abnormality.

Conversely, wider definitions of ME/CFS that do not exclude individuals with psychological/psychiatric reasons for their fatigue reduce the importance of clinical factors (infectious mononucleosis) and increase the importance of psychological factors including premorbid mood disorder and pre-existing psychiatric illness, in predicting their subsequent fatigue syndrome.


Secondly, it is obvious that these definitions do not form a continuum. It is clear when looking at the marked delineation in risk factors between Empirical (clinical, viral) and Oxford defined CFS (psychosocial) that they are looking at completely different illnesses/conditions.

At issue is the effectiveness and wisdom of CBT and GET treatments.

In summary, the evidence for the beneficial effect of GET in CFS/ME (as defined in a way that is compatible with the Empirical criteria referred to above) is not persuasive.

In contrast, research demonstrating clear improvement of mood disorder/psychological conditions utilising exercise regimes are unequivocal.

This only strengthens my view that the term CFS has now become so equivocal if not downright hijacked as to be useless. No study or press item mentioning any study can be taken at face value, due the possibility (and perhaps high probability) that apples will be compared to oranges. It is plausible that there are both apples (e.g., ME/XMVRIDS) and oranges (depression/deconditioning) thrown together slackly (which is not to say maliciously!) in studies, were they will operate to water down the statistics, reducing any clinical insights.

Aside: We don't know if CFS has a complicated explanation or some simple ones

It is easy to get caught up in "its a retrovirus" or "its psychological", or "it can be either".

But it is also possible that some "CFS" is the effect of a complicated chain of complications: maybe you get glandular fever (or Ross River fever, etc), then after that you get a post-viral fatigue, which then kindles some kind of host response change in your endocrine system, which then leads some kind of immunity suppression problem, which then leads to chronic inflammation and cytokine problems, lactic acid problems, allergic reactions, and post-exertion fatigue, further impacted by some XMVR infection, which leads to invalidism and subsequent depression and activity-shyness, many at the same time. I am just lumping various theories together here for effect. But yikes!

In that kind of situation, we may yearn for something that will break the chain at a single point, especially earlier rather than later, but it may be that the better model to think about CFS is of a nuclear reactor generating illnesses, where we need to insert as many rods as possible (treat individual issues) to tame the thing: even if there are good anti-retrovirus medications, we still may need that tonsillectomy, or to be careful with pacing, or to avoid negative people, or to get sustainable occupations and pastimes, etc. (When we look at how successful the management of HIV-positive people's health is nowadays, when it was first regarded as a death sentence, there is good reason for hope: I have two friends who have been HIV positive for more than 15 years, and both have been healthy and well all that time.)

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Kudos to you on doing your homework on this rare disease of ME/CFS.

I worked as an electrical engineer in hardware and software and firmware design for years. ME/CFS just took away all my energy. It's a devastating disease.

I have Chronic Fatigue Syndrome, also Fibromyalgia-every symptom of it. From very severe muscle spasms head to foot, eye pain, skin pain from clothing, etc. With the CFS I sleep 12 to 15 hours. If any less, I must take naps to make up the missed hours.

Where does ME fit in with all this??

I am sorry to hear about your condition, and I hope you are managing to make the best of things. Obviously you are not asking for a diagnosis but a general question to a layman.

I don't think anyone really knows yet. It is a complicated jigsaw puzzle, and the XMRV research may have found the key piece which allows the picture to be constructed...but it may not.

Fibromyalgia is another one of these kind of vague or controversial diagnoses (or, rather, patient classifications) with many of the same kind of symptoms as CFS: with CFS the key symptom is taken to be post-exterional fatigue, with fibromyalgia the key symptom is pervasive and persistent pain.

The vagueness of the classification is little comfort for sufferers, of course, who know it is real.

But CFS and fibromyalgia share a great similarity of associated symptoms (concentration, sleep, depression, irritable bowels, and so on). Like CFS and ME, there have been studies of fibromyalgia sufferers which indicate something odd is going on in a variety of body systems. (There are some differences too: do fibromyalgia sufferers report the recurrent flu-like symptoms that CFS/ME sufferers often have?)

In my mind, I think of a large general class of chronic fatigue/pain syndromes, of which ME, fibromyalgia and perhaps IBS are particular classes based on the strongest symptoms or pathologies.

Overlapping these overlapping classes are names based on patient history: post-viral syndrome, post-polio syndrome, Gulf War syndrome, and so on. But what underlies them (one bug? a class of bugs? monkeys? mice? manatees? allergy? auto-immune malfunction? over-sensitized responses?) is up for grabs. Do they have different causes but take much the same course?

Until we find out the cause (or causes) we are left with just treating the symptoms and co-morbidities: I don't scoff at CBT per se, for that reason, as one aspect of treatment. It is a resolute person indeed who could live with chronic fatigue or chronic pain without it taking over their mental world. But I think CFS sufferers writing online repeatedly make it clear that they don't want a weak treatment to be passed off as a cure: it insults them.

The XMVR research offers hope: it may be a dead-end itself, time will tell, but I think we should welcome the renewed research attention to the family of chronic fatgue/pain/etc syndromes that are so widespread and devastating.

Yes, and the lack of awareness of CFS/ME makes it more difficult than it need be. I hope you get adequate remission at least: it does happen.

I think a person who has recovered from CFS enough to work should negotiate with their employer a position that allows them to pace themselves.

For example, a position with a fixed minimum required hours per month (not inflexible hours per week or inflexible hours per day) that allows ad hoc self-pacing (late starts to ensure adequate rest after bad nights, and days off when needed). For example, 100 hours per month, with extra time allowed as overtime but not expected.

This may rule out supervision positions, client-facing roles, reactive roles, or positions in meeting-mad organizations. Tough. Employers need to be aware that there are good people with these special needs.

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