Don't MEntion Fatigue.
The distinction between ME and CFS and its importance is complex. This is more an opinion piece, potentially in several parts, than a definitive analysis. I have written it to address some issues discussed in several different threads on Phoenix Rising.
Should we focus on the difference between ME and CFS? That depends on the audience. Most people neither want nor need to know. The general public does not care. For them it is better to just give the message that there are a whole lot of very sick people who are being ignored by most doctors and medical researchers, who have little or no funding for a cure, and it is costing everyone a small fortune.
For the medical practitioners there needs to be a message: CFS patients are of several types at least, and different treatments work better for different groups of patients. In time the diagnosis of CFS will disappear, because as we understand what is wrong with people they will be rediagnosed with something else. Every doctor needs to be aware that CFS is temporary diagnosis until there can be a better one.
On a purely technical point, ME is a better diagnosis for several reasons for many of us. Basically it comes down to the technical diagnosis of CFS: CFS is a catch-all used when you can't make a more specific diagnosis. ME is one of the more specific diagnoses that should be exclusory for CFS, a point that has been made repeatedly by a number of advocates. Treatment for ME is therefore going to be more specific to individual patients - the diagnosis will simplify the decision making in the long run and so reduce costs.
I am less than convinced that an ME diagnosis is limited to sudden onset. Many patients seem to have sufficient ME symptoms or findings other than sudden onset. We need more research, but that means more funding, and nobody seems to fund ME reseach any more. A study that is very badly needed is an ME specific proteomic analysis - are the biomarkers in ME the same or different to biomarkers in CCC defined CFS for example?
For politicians, there needs to be another message. This is a growing group of patients who are being ignored, their medical needs not catered for, and no substantive money is being spent on research. We are a drain on our economies, and our treatment is a blight on the moral standing of our countries. Ignoring us is both immoral and an economic mistake. If this turns out to be potentially transmissable (and the evidence accumulates that it is, but the transmission is still not really understood) then its a growing public health crisis. In time they are going to have to deal with it anyway - and whoever is holding the ball when the music stops is in deep political trouble. I think a distinction between ME and CFS is justifiable as a political argument, but that is not a topic I want to pursue today, and the argument will depend on the politics of specific countries.
The science is another issue entirely, and even more complex. There are very important reasons to be both splitters and lumpers, as Mark and uhhhhmmm, the other guy have said recently. ME epidemic cases are a research goldmine.
Forget definitions - local temporal and spatial epidemics give as pure a patient sample as any researcher could hope for. There should be studies on every single epidemic that arises, each with dedicated research funding - which raises important questions. For decades there were regular epidemics. Then they apparently stopped. Why was that? Was it a failure of reporting? Did the epidemics actually stop? Was there a covert or overt decision to stop reporting epidemics? Or is it simply that the sporadic cases have increased in number to the point where defining epidemics has become increasingly difficult? Or maybe some other reason? Perhaps the emphasis on CFS definitions themselves put a break on epidemic reporting, particularly the need to wait six months for diagnosis? Could this be a critical reason why we should be using ME as a primary diagnosis? Could it be a reason why the CFS diagnosis was promoted so strongly by the CDC, it prevents the reporting of the epidemics?
On the other hand, research grants are about perception as much as substance. This is a political issue as much as a scientific one. We are not a favoured research area. The almost complete absence of substantive research funding, ever, is a clear indicator of that. While CFS has been out of favour, ME is almost forgotten. How many grants are now being awarded to research ME?
PACE: The LEAD standard.
I wish to write about PACE and research definitions and protocols, as a demonstration of some of the issues I would like to raise. The PACE study was a perfect example of what could have been a good study, but absence of recognition of the research cohort issues and existing biomedical science turned a potential "gold" standard study into a "lead" standard study.
I vaguely recall reading an article in which Fukuda was asked about criteria and so on. He made two points - one was that exclusionary criteria are only valid if they explain all the symptoms. If substantial symptoms remain unexplained, the criteria were not exclusory. The second was the 1994 CFS definition was an inclusive group for research purposes. It was his intention that this group would be investigated for subgroups, and those subgroups would be researched.
One of the problems we face is that there is no definitive ME/CFS research standard. Organizations like the WHO or IACFSME are really the only type of organization that can define something like this, and it does not appear that either is willing or cabable of doing so. I am not talking about just case definition, which the CCC at least tried to address, I am talking about entire research protocols. Maybe we should be aiming for a separate international organization to examine this, if existing ones cannot do so? On the other hand the IACFSME or WHO might be able to do this if funding were available.
To my understanding a broad research definition such as Fukuda (or even Oxford) is intrinsically no bar to good science. This really just defines how wide a net you draw in recruiting patients. What is a bar to good science is deciding that such recruiting criteria are definitive of a single disorder before the science is done, and in deciding to only investigate it using a unifying hypothesis without adequately testing that hypothesis - which is a problem with many of the biopsychosocial hypotheses.
A gold standard research protocol, unless it were for a specific single epidemic, would both lump and split. This is what PACE was supposed to do, but never did. If you are going to recruit a large and broad cohort of patients, something there is usually not enough funding to do, then it is a great opportunity to get many different analyses from the one study. Every single patient should have had extensive testing sufficient to be diagnosed under every major diagnostic criteria there are.
At the very least this would include a brain MRI, a full neuropsychological workup, and the complete Stevens protocol with pre- and post-exercise cytokine panels, and NK function tests using today's science. Of course PACE was before we had some of these breakthoughs, which is another problem with it - the study took so long that the science it might have been based on (which they still failed to use) was obsolete before it finished.
What they could have used was activity data, which they started with then abandoned. To my way of thinking, this was either a failure to perform adequate science, or an overt distortion of the study. Which of the two it was is for historians or a Royal Commission to decide.
The PACE study could have done a full neuropsychological workup and MRI imaging. They could have had mandatory sleep studies, and tilt table tests. They failed to do any of this. The cytokine issues, NK cell issues, and exercise retesting issues were much less obvious when PACE was designed. Leaving out these issues is not about science, it is about politics, conducting a study which is appealing to the current UK medical protocols and prejudices on CFS. It is an attempt to simplify complex issues by overlooking conflicting data, not addressing it.
I want to talk about a gold standard version. The goal would be that every patient had enough investigation to diagnose them using a range of definitions, both CFS and ME definitions, from Ramsay to CCC. They could have run their study, then done different post-study analyses. Those with Ramsay ME get one set of results, CCC another, Oxford another, etc. This would have given us much more data, and helped validate different concepts of the disorder. This opportunity was completely missed. Basing the entire study almost entirely on a highly subjective and heterogenous symptom like fatigue is just begging for confusion. At the very least, they could have done the basic investigations and then just published a study focussed on Oxford defined fatigue patients, but made the raw data available so that any researcher could take out specific subgroups and run separate analyses. This could have included Ramsay defined ME. That way the cost and resource issues could have been spread worldwide and over time. This was another opportunity missed.
A big issue with this was funding - no surprise there. In the UK the kinds of investigation necessary is unfunded and against official policy. So very few patients would have had the necessary investigations prior to running the study. So each patient would have had to have had a full workup - hundreds of MRIs, neuropsych tests, exercise physiology workups, sleep studies, tilt table tests and so on. This would have been very costly in time, money and resources, and completely beyond the scope of purely psychiatric or psychological investigators. Their study should have been multidisciplinary - but where were the exercise physiologists, the sleep labs, the neuroscientists, the immunologists?
There is also the question of severity stratification. A six minute walking test, really? Where are the patients who cannot get out of bed? Those who cannot walk a hundred meters without passing out? The PACE study excludes such patients, and I am not sure this type of study could ever be expanded to these patients. How do you tell someone who can barely move to exercise - ask them to imagine they are pumping dumbells? How do you engage in cognitive therapy with someone who cannot read, can barely speak, can't understand what you said and will not remember it anyway?
They failed to deal with secondary symptoms, especially severe ones. Syncope was ignored, as was muscle and neurological pain, or neurocognitive disturbances. This problem again occured in reporting adverse events. It is not enough to report severe adverse events. They should have many adverse event categories, including severity of events, and reported on every cohort subgroup separately. That way negative events could be associated with each type of patient and treatment.
It could be argued that the PACE study was necessarily limited in scope for financial or scientific reasons. That is another issue I might write about later, but I don't buy it. If they want to claim a definitive study, then they need to undertake a definitive study - otherwise they are only investigating a limited hypothesis, and even that they failed to do using the best available science when the study was designed.
So a perfect PACE study would have given us a lot of data on CFS (Oxford), ME (Ramsay) and so on. They failed to use the opportunity to do so. We don't just need definitive diagnostic protocols - we need some international agreement, or at least discussion, on what a gold standard research protocol would be, from patient recruitment to post-study analyses. At the very least epidemic cases need to be considered as distinct groups, separated for special attention with dedicated funding. Also, any stratification into subgroups needs to address different definitions of both ME and CFS. This is the minimum scientific requirement until we have a simple definitive diagnostic test for every subgroup - but it is quite possible that definitive tests will simply remove those subgroups to a differential diagnosis.
Otherwise a study needs to be clear that it is only on a specific subgroup - so where are the dedicated ME CBT studies? The ME subgroup in the PACE study were done using a modified version of the London definition, which itself is not widely accepted. In the end the PACE study has apparently been claimed to apply only to chronic fatigue patients with no substantial additional symptoms - but this is said in one place, and universal applicability is discussed elsewhere. Confusion abounds.
Semantic games are standard for the biopsychosocial research into ME/CFS, or as they like to call it CFS/ME. They use a local definition for CFS, the Oxford definition. When they use the Fududa definition, they do not use it using accepted protocols. The definition of ME used in the PACE trials was modified. They tested an alternative exercise protocol and called it Adaptive Pacing, but it resembles no other pacing protocol. They redefine things, then use the new definition in their study. Then they go back and claim the results are applicable using the original terms - CFS, ME, pacing etc. This is a a gross failure in logic, or a deliberate attempt to deceive, or both. It is more spin than science.
I don't know if I will write a second part to this blog. There are certainly many issues that I haven't touched on. I might get around to it, on another day when I have energy to spare.
Of course in the meantime if the research leads us to talk of virally induced brain stem damaged patients, NK cell dysfunction syndrome or HGRV infections instead, we will have better subgroups for study anyway, and the biopsychosocial movement can go back to their study of idiopathic chronic fatigue.
The distinction between ME and CFS and its importance is complex. This is more an opinion piece, potentially in several parts, than a definitive analysis. I have written it to address some issues discussed in several different threads on Phoenix Rising.
Should we focus on the difference between ME and CFS? That depends on the audience. Most people neither want nor need to know. The general public does not care. For them it is better to just give the message that there are a whole lot of very sick people who are being ignored by most doctors and medical researchers, who have little or no funding for a cure, and it is costing everyone a small fortune.
For the medical practitioners there needs to be a message: CFS patients are of several types at least, and different treatments work better for different groups of patients. In time the diagnosis of CFS will disappear, because as we understand what is wrong with people they will be rediagnosed with something else. Every doctor needs to be aware that CFS is temporary diagnosis until there can be a better one.
On a purely technical point, ME is a better diagnosis for several reasons for many of us. Basically it comes down to the technical diagnosis of CFS: CFS is a catch-all used when you can't make a more specific diagnosis. ME is one of the more specific diagnoses that should be exclusory for CFS, a point that has been made repeatedly by a number of advocates. Treatment for ME is therefore going to be more specific to individual patients - the diagnosis will simplify the decision making in the long run and so reduce costs.
I am less than convinced that an ME diagnosis is limited to sudden onset. Many patients seem to have sufficient ME symptoms or findings other than sudden onset. We need more research, but that means more funding, and nobody seems to fund ME reseach any more. A study that is very badly needed is an ME specific proteomic analysis - are the biomarkers in ME the same or different to biomarkers in CCC defined CFS for example?
For politicians, there needs to be another message. This is a growing group of patients who are being ignored, their medical needs not catered for, and no substantive money is being spent on research. We are a drain on our economies, and our treatment is a blight on the moral standing of our countries. Ignoring us is both immoral and an economic mistake. If this turns out to be potentially transmissable (and the evidence accumulates that it is, but the transmission is still not really understood) then its a growing public health crisis. In time they are going to have to deal with it anyway - and whoever is holding the ball when the music stops is in deep political trouble. I think a distinction between ME and CFS is justifiable as a political argument, but that is not a topic I want to pursue today, and the argument will depend on the politics of specific countries.
The science is another issue entirely, and even more complex. There are very important reasons to be both splitters and lumpers, as Mark and uhhhhmmm, the other guy have said recently. ME epidemic cases are a research goldmine.
Forget definitions - local temporal and spatial epidemics give as pure a patient sample as any researcher could hope for. There should be studies on every single epidemic that arises, each with dedicated research funding - which raises important questions. For decades there were regular epidemics. Then they apparently stopped. Why was that? Was it a failure of reporting? Did the epidemics actually stop? Was there a covert or overt decision to stop reporting epidemics? Or is it simply that the sporadic cases have increased in number to the point where defining epidemics has become increasingly difficult? Or maybe some other reason? Perhaps the emphasis on CFS definitions themselves put a break on epidemic reporting, particularly the need to wait six months for diagnosis? Could this be a critical reason why we should be using ME as a primary diagnosis? Could it be a reason why the CFS diagnosis was promoted so strongly by the CDC, it prevents the reporting of the epidemics?
On the other hand, research grants are about perception as much as substance. This is a political issue as much as a scientific one. We are not a favoured research area. The almost complete absence of substantive research funding, ever, is a clear indicator of that. While CFS has been out of favour, ME is almost forgotten. How many grants are now being awarded to research ME?
PACE: The LEAD standard.
I wish to write about PACE and research definitions and protocols, as a demonstration of some of the issues I would like to raise. The PACE study was a perfect example of what could have been a good study, but absence of recognition of the research cohort issues and existing biomedical science turned a potential "gold" standard study into a "lead" standard study.
I vaguely recall reading an article in which Fukuda was asked about criteria and so on. He made two points - one was that exclusionary criteria are only valid if they explain all the symptoms. If substantial symptoms remain unexplained, the criteria were not exclusory. The second was the 1994 CFS definition was an inclusive group for research purposes. It was his intention that this group would be investigated for subgroups, and those subgroups would be researched.
One of the problems we face is that there is no definitive ME/CFS research standard. Organizations like the WHO or IACFSME are really the only type of organization that can define something like this, and it does not appear that either is willing or cabable of doing so. I am not talking about just case definition, which the CCC at least tried to address, I am talking about entire research protocols. Maybe we should be aiming for a separate international organization to examine this, if existing ones cannot do so? On the other hand the IACFSME or WHO might be able to do this if funding were available.
To my understanding a broad research definition such as Fukuda (or even Oxford) is intrinsically no bar to good science. This really just defines how wide a net you draw in recruiting patients. What is a bar to good science is deciding that such recruiting criteria are definitive of a single disorder before the science is done, and in deciding to only investigate it using a unifying hypothesis without adequately testing that hypothesis - which is a problem with many of the biopsychosocial hypotheses.
A gold standard research protocol, unless it were for a specific single epidemic, would both lump and split. This is what PACE was supposed to do, but never did. If you are going to recruit a large and broad cohort of patients, something there is usually not enough funding to do, then it is a great opportunity to get many different analyses from the one study. Every single patient should have had extensive testing sufficient to be diagnosed under every major diagnostic criteria there are.
At the very least this would include a brain MRI, a full neuropsychological workup, and the complete Stevens protocol with pre- and post-exercise cytokine panels, and NK function tests using today's science. Of course PACE was before we had some of these breakthoughs, which is another problem with it - the study took so long that the science it might have been based on (which they still failed to use) was obsolete before it finished.
What they could have used was activity data, which they started with then abandoned. To my way of thinking, this was either a failure to perform adequate science, or an overt distortion of the study. Which of the two it was is for historians or a Royal Commission to decide.
The PACE study could have done a full neuropsychological workup and MRI imaging. They could have had mandatory sleep studies, and tilt table tests. They failed to do any of this. The cytokine issues, NK cell issues, and exercise retesting issues were much less obvious when PACE was designed. Leaving out these issues is not about science, it is about politics, conducting a study which is appealing to the current UK medical protocols and prejudices on CFS. It is an attempt to simplify complex issues by overlooking conflicting data, not addressing it.
I want to talk about a gold standard version. The goal would be that every patient had enough investigation to diagnose them using a range of definitions, both CFS and ME definitions, from Ramsay to CCC. They could have run their study, then done different post-study analyses. Those with Ramsay ME get one set of results, CCC another, Oxford another, etc. This would have given us much more data, and helped validate different concepts of the disorder. This opportunity was completely missed. Basing the entire study almost entirely on a highly subjective and heterogenous symptom like fatigue is just begging for confusion. At the very least, they could have done the basic investigations and then just published a study focussed on Oxford defined fatigue patients, but made the raw data available so that any researcher could take out specific subgroups and run separate analyses. This could have included Ramsay defined ME. That way the cost and resource issues could have been spread worldwide and over time. This was another opportunity missed.
A big issue with this was funding - no surprise there. In the UK the kinds of investigation necessary is unfunded and against official policy. So very few patients would have had the necessary investigations prior to running the study. So each patient would have had to have had a full workup - hundreds of MRIs, neuropsych tests, exercise physiology workups, sleep studies, tilt table tests and so on. This would have been very costly in time, money and resources, and completely beyond the scope of purely psychiatric or psychological investigators. Their study should have been multidisciplinary - but where were the exercise physiologists, the sleep labs, the neuroscientists, the immunologists?
There is also the question of severity stratification. A six minute walking test, really? Where are the patients who cannot get out of bed? Those who cannot walk a hundred meters without passing out? The PACE study excludes such patients, and I am not sure this type of study could ever be expanded to these patients. How do you tell someone who can barely move to exercise - ask them to imagine they are pumping dumbells? How do you engage in cognitive therapy with someone who cannot read, can barely speak, can't understand what you said and will not remember it anyway?
They failed to deal with secondary symptoms, especially severe ones. Syncope was ignored, as was muscle and neurological pain, or neurocognitive disturbances. This problem again occured in reporting adverse events. It is not enough to report severe adverse events. They should have many adverse event categories, including severity of events, and reported on every cohort subgroup separately. That way negative events could be associated with each type of patient and treatment.
It could be argued that the PACE study was necessarily limited in scope for financial or scientific reasons. That is another issue I might write about later, but I don't buy it. If they want to claim a definitive study, then they need to undertake a definitive study - otherwise they are only investigating a limited hypothesis, and even that they failed to do using the best available science when the study was designed.
So a perfect PACE study would have given us a lot of data on CFS (Oxford), ME (Ramsay) and so on. They failed to use the opportunity to do so. We don't just need definitive diagnostic protocols - we need some international agreement, or at least discussion, on what a gold standard research protocol would be, from patient recruitment to post-study analyses. At the very least epidemic cases need to be considered as distinct groups, separated for special attention with dedicated funding. Also, any stratification into subgroups needs to address different definitions of both ME and CFS. This is the minimum scientific requirement until we have a simple definitive diagnostic test for every subgroup - but it is quite possible that definitive tests will simply remove those subgroups to a differential diagnosis.
Otherwise a study needs to be clear that it is only on a specific subgroup - so where are the dedicated ME CBT studies? The ME subgroup in the PACE study were done using a modified version of the London definition, which itself is not widely accepted. In the end the PACE study has apparently been claimed to apply only to chronic fatigue patients with no substantial additional symptoms - but this is said in one place, and universal applicability is discussed elsewhere. Confusion abounds.
Semantic games are standard for the biopsychosocial research into ME/CFS, or as they like to call it CFS/ME. They use a local definition for CFS, the Oxford definition. When they use the Fududa definition, they do not use it using accepted protocols. The definition of ME used in the PACE trials was modified. They tested an alternative exercise protocol and called it Adaptive Pacing, but it resembles no other pacing protocol. They redefine things, then use the new definition in their study. Then they go back and claim the results are applicable using the original terms - CFS, ME, pacing etc. This is a a gross failure in logic, or a deliberate attempt to deceive, or both. It is more spin than science.
I don't know if I will write a second part to this blog. There are certainly many issues that I haven't touched on. I might get around to it, on another day when I have energy to spare.
Of course in the meantime if the research leads us to talk of virally induced brain stem damaged patients, NK cell dysfunction syndrome or HGRV infections instead, we will have better subgroups for study anyway, and the biopsychosocial movement can go back to their study of idiopathic chronic fatigue.
