Post-Exertional Malaise : The Hallmark of Chronic Fatigue Syndrome

I was going to post a comment on a particularly hateful blog about the difference between Chronic Fatigue Syndrome (CFS) and ordinary fatigue, but it grew into a much longer article, so I decided to blog it myself. Basically, it boils down to a debate. There are two definitions of CFS: one, promoted by the Centers for Disease Control (CDC) and popular in Europe, is that CFS is fatigue principally of psychiatric origin. People with certain physical findings are ruled out of diagnosis of CFS. In the UK, it is summarized as patients having 'inappropriate illness beliefs.' In other words, because they think they're sick, they're making themselves sick. It's the somatization disorder par excellence. The other definition is the Canadian Clinical Consensus (CCC), which requires certain physical findings in addition to fatigue, and rules out certain psychiatric conditions. A substantial body of research supports the biomedical definition, which includes immunological, neurological, and hormonal abnormalities. However, the CDC is a government agency and major funder of research, so its view dominates.

Recently this all erupted in the news when researchers at the Whittemore-Petersen Institute (WPI) published research in the journal 'Science' showing a strong link between CFS and the newly discovered retrovirus XMRV. CFS patients latched onto this -- the science is good, and while whether and what kind of disease XMRV might cause in humans is not known, the problems it causes in animals parallel CFS. Thus many people are hoping that the cause of CFS has been found, and that it is XMRV. That patients are hoping to find out they have a serious potentially fatal retrovirus is a sign of how desperate they are -- a diagnosis means dignity, treatment, and a hope of a better quality of life, in spite of the risks.

Unfortunately, several studies since then find no link between XMRV and CFS. In fact, they don't even find XMRV in the general population. However, those negative studies use a definition derived from the CDC definition. WPI used the CCC definition. Thus those patient cohorts are not congruent; the CDC definition would rule out almost anybody diagnosed on the CCC definition. Do severely fatigued psychiatric patients have 'CFS'? If XMRV causes CCC defined CFS, can patients who do not meet the CCC definition be expected to have XMRV?

Obviously, there are two problems: patient cohorts not the same, and the link between CFS and XMRV is not yet proven. Maybe there is something else that causes people with CCC CFS to be vulnerable to XMRV -- XMRV might just be an opportunistic infection attacking CFS patients who are immunocompromised. Maybe XMRV is prevalent in North America, but not Europe.

However, a recent German study of immunocompromised people with respiratory ailments found that 10% of those people have XMRV. So apparently, XMRV is in Europe, after all. If it's in Europe, why didn't the negative studies find it? Presumably random luck would mean that a handful of patients tested would have it, just because a random number of anybody tested would have it. That leads to accusations of bad science and that the negative studies, carried out largely by adherents of the psychiatric definition, were deliberately trying to not find it. This is nonsense, but clearly, researcher bias must be considered; if you've staked your career on a psychiatric definition, you're going to do science looking to support your hypothesis. On the other hand, the same bias can be imputed to to biomedical researchers. If you've staked your career on a physical cause, that's what you're going to look for. The difference is, there's a considerable body of evidence in support of the physical hypothesis, so it's not really a matter of opinion.

The debate rages. CFS-deniers would have us believe that CFS patients are a bunch of crazy lunatics with Munchhausen's Syndrome, pretending to have a Really Important Disease like XMRV to get attention and avoid responsibility for their own laziness, while CFS-defenders are shrilly screaming, "You ignorant *#@*+ are perpetrating genocide against horribly ill people! " (The genocide claim arises from some highly publicized cases in the UK in which people with CFS were committed to mental institutions and denied medical treatment and later died or committed suicide. Some of the conditions that biomedical medical researchers have found to be more common in patients with CFS, such as heart failure and lymphoma, certainly indicate that patients' lives are at risk.)

The 'fatigue' in Chronic Fatigue Syndrome is not normal fatigue, and differs from fatigue in depression, multiple sclerosis and other diseases. Specifically, the fatigue in CFS is all out of proportion to the muscle effort involved, and it persists for an extended period afterwards. This is known as 'post-exertional malaise' and is the hallmark of CFS.

Good, solid, medical research illustrates how CFS patients differ from ordinary persons. Dr. Light tested several groups of patients, including healthy controls, people with CFS, and people with MS. They performed moderate exercise and were tested before and at intervals afterwards. The blood chemistry of participants with MS is slightly elevated compared to normals, but the blood chemistry of people with CFS is like a volcano going off -- far  beyond both normals and people with MS. Further, patients' subjective reports of fatigue corresponded with the laboratory results. In others words, the more fatigued a patient reported themselves to be, the higher their laboratory results. Ergo, the fatigue in CFS is not just because the patients are unwell, fatigue IS the illness.

You may read a good discussion of Dr. Light's work here: http://aboutmecfs.org/Conf/IACFS09Surprise.aspx

Testing all these items is not practical in a family medical practice, so this is not going to offer a useful diagnostic test, but does it illustrate exactly how CFS patients are different from both healthy people and other unwell people. It shows very clearly that these patients have an abnormal fatigue that is strikingly different from any other disorder, that it is physical, that CFS patients' self-assessment of their fatigue corresponds with testable biological changes (they do not have 'inappropriate illness beliefs' -- their beliefs are realistic assessments of their condition), and that offers some insight into the nature and operation of the fatigue, and suggests avenues for further research and treatment.

Specifically, it appears that these patients are not experiencing muscle fatigue, which is the usual cause of ordinary fatigue, but that they are experiencing abnormal function in either the nervous system, or in the linkages between the nervous system and the muscles. Not being a scientist I do not quite understand this part of the discussion, but it does accord with my personal observations: I am not 'muscle tired' when engaged in physical activity, and in fact, my muscles seem willing to do a great deal more, but that somewhere between my brain with its desire to do more and my body's ability to respond is a dysfunction so that I experience fatigue, weakness, loss of coordination, and other impairments that prevent me from doing what I greatly desire to do. I feel like I'm wearing a lead suit.

Or look at it this way: on a good day I can bound up the steps two at a time, but during post-exertional malaise, those steps are Mt. Everest. On a bad day, I KNOW that I am physically capable of bounding up those steps (because I did it yesterday), but now I can't. Merely lifting my foot and not tripping over the step is a major undertaking.

I have learned to pace myself: I can perform light activity all day long, but if I burn up the same number of calories in an intense burst of activity lasting 20-30 minutes, and I am prostrate afterwards, and that fatigue (post exertional malaise) lasts 3-4 days. Intense bursts of effort must be very short, and I must have a rest period afterwards; the key to being able to keep going is to make certain I do not build up an energy deficit. In other words, I must keep my energy expenditure to the level my body is able to replace because once I've exhausted it, it's not coming back. In a normal person recovery is quick, generally less than 24 hours, even for a major physical activity, but in CFS it takes days, weeks, or months.

An example: A normal person rides their bicycle for half an hour. They come home, take it easy for a bit, and later that afternoon do it again. If a person has CFS, they ride their bicycle for half an hour, come home, go to bed, and get up three days later. They WANT to get up, and feel guilty as hell for not getting up, so they drag themselves out of bed to open a can and call it dinner, then crawl back in bed.

This disease is not at all confusing -- work like Dr. Light's is very clear, and so are many other pieces of biomedical research. What is confusing is why so many people willfully choose to refuse to understand the difference between the Canadian Clinical Consensus and the CDC versions. It really doesn't matter which CDC definition you use, they CDC does not distinguish between fatigue and Chronic Fatigue Syndrome (CFS).

The CDC's definitions have not yet helped anyone as far as I can see, and does not offer any roadmap about how to make progress in studying CFS or helping patients with CFS; therefore it has no utility for any practical person. The Canadian Clinical Consensus offers possibilities to explore and follow up on, both in a research setting and in a general practice setting -- doctors can, for example, investigate whether their patients have POTS or heart failure or other conditions discussed in the CCC version, and if so, send them for treatment of those conditions. While that may not change their CFS, presumably by having these conditions treated the patient will feel better and have a better quality of life. That's useful, practical, and constructive.

Kill the CDC definitions, and adopt the Canadian Clinical Consensus. Then there will be no more arguments over patient cohorts, and no more confusion about how to best pursue the study and treatment of CFS. Patients can reasonably hope to get assistance and have an improvement in their quality of life, even if a cure is a long way off. In a way, the quest for 'The Cause' of CFS is a red herring -- we know enough right now that we can improve the lives of patients with CFS. We should be acting on this knowledge. Dropping the CDC definition will allow both the care of patients and the research to move forward.

As for myself, I am a tall ship sailor. This is a physically demanding activity, but while it is more demanding that the ordinary activities of most people, it's not as hard as you might think. And it's not as hard as the newbies think :) For one thing, it intersperses short intense activities with periods of light activity, and for another, you're not alone. You have your shipmates. You're not performing at the same intensity all the time -- you have help. Likewise, if you don't think you're up to a particular exertion, you can ask your shipmates to 'bear a hand' and get some help, and since there are a number of activities to be performed in any given evolution on board, you can volunteer for an activity within your current ability. Thus, the positive cooperative efforts and varied tasks of a tall ship allow me to manage my activity level and match it to the tasks at hand. I also volunteer for tasks -- like washing dishes -- that other people don't like that are within my energy level, and which win me brownies points, so that when I need to beg off of a task, I'm not seen as a shirker.

The other wonderful thing about the ship: sleep is sacrosanct. When you're not working, you're expected to go to bed. This is the complete opposite of the real world, where if you're in bed, you're a lazy bum. Sleep is protected on the ship. Further, the work periods are short: we stand Swedish watches which means work periods of either six or four hours, with rest periods in between. I have discovered that six hours is about the limit of my activity; at the 5-6 hour mark I find I'm tapped out. If I keep working beyond that, as in a typical 8 hour job, my last 2 hours are low productivity and I'm exhausted when I get home. Done day after day as in a standard job drives me into the ground and eventually to a state of collapse. Before the ship I had already learned that working a short shift, then napping, and working a few more hours enabled me to be much more productive than a single long shift. In other words, 4 nap 4 = more work done than 8 straight. Unfortunately, employers object if you spend a couple of hours sleeping at work. (Lunch naps help, but they aren't long enough.)

Normal people aboard the ship are not used to this rhythm and get very tired; that means they wind up feeling as tired on a voyage as I do all the time. Ergo, I can admit to fatigue and no one will accuse me of being lazy or shirking or not trying hard enough. On the contrary, they are all just as tired as I am. We can share our experiences, sympathize with one another, and bond over it. This is the opposite of the 'real world.' The difference is, once back ashore, I'm going to spend a couple of weeks recuperating, while they're going to spend a couple of days. Because it's a volunteer position, I do not have to keep showing up at work day after day and can take time to recuperate.

However, I also can't work a real job while doing this; it takes up too much time and energy. Eventually I will use up my savings and have to get a real job. I'm dreading it. Working a tall ship is much better for me than working at Wal-mart, my previous job. The cooperative work environment, the respect given to the crew, the division of labor based on ability rather than quotas, and the esprit de corp, make it a superior work environment. Of course, it's also a demanding environment with no privacy, sea sickness, and blistering sun day after day combined with a risk of sinking, but I can live with that.

~K~

XMRV Revisited

Recently Simon Wessly et al, authors of the PLOS article I criticized in a previous post, have fired back at criticisms they are receiving from around the world regarding their patient cohort. Since I believe in giving the Devil his due, I will briefly summarize their reply. They specifically addressed the criticism that their patients are not typical of CFS patients, and that their patients are purely psychiatric cases. They identify several biologically anomalies in their patients, so it appears that not all their patients are 'pure' psychiatric patients. Based on the information presented in their article, it appeared that they had screened out all patients with documented physical anomalies. I don't know enough about the medical details to assess whether the biological anomalies they note are the same as those found by other researchers or whether they are significant in CFS. However, they explicitly state that they do NOT use the Canadian Clinical Consensus because they don't how to use it. (???!) Given that the Whittemore Peterson Institute DOES use the Canadian Clinical Consensus, it is clear that the patient cohorts necessarily differ in significant ways. Different patient cohorts = different study outcomes. No surprise there. The PLOS paper says nothing about the science done by the Whittemore Peterson Clinic. As long as they don't claim their study is a replication study (it isn't), there's nothing to get excited about.
I salute the authors of the PLOS article for defending their patients and asserting them to be as worthy of medical care and research as other patients. Unlike some critics, I don't think they're a cynical bunch of bastards making money for insurance companies off the bodies of their patients. I believe they actually do care about their patients. I think they're wrong-headed in how they go about it. I've met their kind of doctor before: absolutely unshakeable in their certainty that their medical degree means they're right and their patient is wrong.


I also salute them for detecting celiac disease in about 2% of their patients; this is a pernicious disorder that is hard to identify and can make a person absolutely miserable if not treated. On the other hand, such patients are then excluded from a diagnosis of CFS, and some studies have shown an association of gluten intolerance with CFS. They also exclude cancer patients from a diagnosis of CFS, and other research has shown that patients with CFS are at an elevated risk of developing cancer. Thus they have excluded two populations of patients that are reasonably included in CFS research. 


However, the WPI makes no statement regarding celiac disease, so we don't know if it played a role in their patients, either. The WPI statements about cancer patients have been confusing; I have tried to track it down, and I believe they have said that the rate of lymphoma in CFS patients is one of the things that tipped them to look for XMRV, but that they did not include cancer patients in the cohort of 101 patients in their original study. Thus it appears that the WPI and UK patients are similar in this regard. Nonetheless, the utilization of the Canadian Consensus by the WPI and the utilization of the older Fukuda criteria by the UK study are dramatic differences in CFS definition and patient selection which render their study outcomes irrelevant to one another.
Above and beyond the medical implications for the public health that XMRV and CFS pose, the drama being played out in the usually sedate world of medical research is fascinating in and of itself. Somebody is going to take an Oedipal fall before this is all over, and like Oedipus, nobody is going to cry for them when it happens. It's like watching a very close football match, except in this case the outcome actually matters. My health--and yours-depends on it.

XMRV, Chronic Fatigue, and Controversy

I've been following the XMRV research in detail. Researchers at the Whittemore-Peterson Institute affiliated with the University of Nevada have identified a strong link between CFS and XMRV. Some scientists have speculated (and have clearly identified it as a speculation) that it is the cause of CFS. All scientists who have made such speculations have stressed that we are in the early stages of research and that further research is needed.

Recently they were challenged by a paper from the UK by Simon Wessly et al published in PLOSOne. PLOSOne is a CROCK. PLOSOne is a pay-to-publish site with minimal peer review. With $1365 you too can publish your science there. I went and looked up their submission guidelines and policies myself. If the authors really did good science, why didn't they publish it in a normal medical or scientific journal with rigorous standards and a robust peer review process?

That paper, which purports to find no XMRV in 186 'CFS' patients has numerous screaming flaws; the biggest one of which is that the do NOT use the same definition of 'CFS' as the WPI research. Further, there's no healthy controls in the research and they didn't search for the same DNA sequence as the WPI. In other words, it looks like science, but it isn't. If I report apples, and you search for oranges and don't find them, it's meaningless. All it really proves is that apples aren't oranges.

WPI explicitly uses the Canadian Clinical Consensus, which is the gold standard in medical description of CFS. Here's a page with links to the Canadian Consensus: http://www.cfids-cab.org/MESA/ccpc.html -- If you have Chronic Fatigue Syndrome, think you might, or know somebody that does, the Canadian Clinical Consensus will be very helpful.

The UK paper does not use the Canadian consensus; they use the Oxford/CDC definition, which explicitly excludes anyone with a physical contribution to their fatigue. In other words, the WPI patients, which meet the Canadian consensus, all have demonstrable physical aspects to their illness, and therefore would not and could not be diagnosed with CFS in the UK.

The UK cohort consists of fatigued psychiatric patients, although it does excludes some psychiatric conditions as per the Fukuda definition. Note that their paper does not claim to follow the Fukuda definition, it merely claims to exclude the same exclusions that Fukuda does. Some people have said that both WPI and UK use Fukuda standards --no, the UK study does not.

Further more, the UK patients are all in routine treatment through the chronic fatigue center at Kings College. In other words, these are people who are willing to go along with a psychiatric diagnosis and treatment. People who don't benefit from psychiatric treatment or who believe their condition is physical, not mental, are not going to be members of this clinic!

Above and beyond that, the UK research did not follow the exact same procedures as the WPI research, which is essential in an replication study. The UK study also did NOT include healthy controls. Ergo, they have foregone one of the essential elements of sound scientific testing. They assert that their patients are typical of the UK -- they're not.

There's a lot of people in the UK, including scientists, who believe in a physical explanation and have produced research and documentation in support of their view. We cannot generalize from one clinic that specializes in somatoform CFS to the rest of the UK.

Not yet published is information about UK patients participating in testing who have gone through their medical doctors rather than psychiatric services. These Individuals participated in a group that sent their blood samples to the WPI to be tested. Some individuals have received their lab reports and posted their results online; they are XRMV+. This is a small number of people, so we don't know how many UK patients participated or what the over all result it, but clearly, XMRV does occur in some patients in the UK. Thus, the Wessly et al conclusion that XMRV is not in the UK is wishful thinking at best.

XMRV is known to cause disease in animals: nasty ones, such as immune and endocrine disorders, and cancer, such as lymphoma. While it is not known exactly what it does to humans, we can expect that it will do similar things to us as to other mammals. CFS patients have already been shown to have a higher risk of cancer, especially lymphoma. The symptoms of CFS (Canadian Consensus) are definitely like the symptoms of XMRV in animals. Ergo, it is plausible to suspect that it causes CFS. It remains to be be proven, but it's a promising line of research and more scientists around the world are after it.

'CFS' has been applied to a sloppy variety of conditions by many writers who choose to ignore and cherry pick the scientific evidence; but that doesn't mean that it isn't real or that XMRV is irrelevant.

The WPI researchers have proposed the name XAND for X-associated neuroimmune disorder for the Canadian consensus disease if the XRMV connection holds out. If Wessly and the other advocates of 'erroneous illness beliefs' want to hang onto CFS, let them. I'll get tested for XMRV and treated by medical doctors for XAND.

The UK paper does do one great good thing. It makes clear that two very different patient cohorts are being lumped together under the label 'CFS'. The authors appear to be unaware of that result; but once you've studied all the evidence in this and many other pieces of research, it is very clear that there are at least two different syndromes lumped together.

Of course, we already knew that. A study done in the UK by Dr. Kerr compared patients with Q fever, CFS, depression, and healthy controls. They fell into two clusters: Q fever and CFS shared many genetic anomalies (84-88), while depression and normals had very few to none (0-5).

However, nobody paid very much attention to any of the research about CFS until now. The only reason, I'm sorry to say, why this matters, is that the WPI study found that 3.7% of healthy controls were XMRV+. This finding has profound implications for the blood supply and public health. That's what made the medical establishment and government agencies sit up and take note at last. Oddly enough, they had previously ignored Japanese research that found XMRV in 2.7% of healthy controls. (This little tidbit is actually in the Wessly et al paper mentioned above!)

They're not terribly concerned about the CFS people, but they do care very much about the idea that the people who vote them into office might, say, be getting infectious cancers from the blood supply and passing them onto to others through saliva or blood... That's a nightmare scenario that must make you break out in a cold sweat if you were supposed to be a public health agency and you haven't done squat about CFS for the last 25 years...

Of course, we don't really know if that's possible, but it's not far-fetched. XMRV has been detected in saliva and blood, and is capable of transmitting infection via blood in the laboratory. Dr. Peterson in his comments at the CFSAC meeting told about a patient of his that got XMRV via blood transfusion--he has before and after blood samples.

XMRV causes cancer in animals and was discovered in connection with prostate cancer. Intimates of people with CFS are somewhat more likely than the general public to have CFS. One study of Gulf War Syndrome found that in a subset of parents with CFS, their children were much more likely to have autism.

On the other hand, German and Irish researchers have not found XMRV in prostate cancer. They have used much larger samples than the US research. Why? Some speculate that their methods are not capable of detecting it, which they vigorously deny. They prefer to speculate that XMRV is regional, and thus is found in the US but not Europe. That doesn't make much sense, either, given that viruses travel very well. Although viruses are more common in some areas than others, they still exist everywhere. On the other hand, that XMRV has been detected in Japanese and American populations does suggest another possibility: genetic susceptibility.

Japanese and Native Americans are descended from a common ancestor somewhere between 10,000 - 25,000 years ago. If XMRV or a genetic susceptibility entered the Asian genome before the population of America, people with Asian and Native American ancestry would be more likely to have XMRV than Europeans. This is not unusual; Africans are much more likely to get sickle cell anemia, for example. Still, no information has been provided about the ethnic makeup of the people who are XRMV+, so this is pure speculation. It also points out that race and ethnicity should not be ignored when conducting scientific research.

More research is under way, and more papers will be appearing over the course of the next year. It's an interesting topic with significant implications for the health of all of us.