Archived Comments for:
Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
As a former archivist who has read almost all publications on myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), I have come across papers linking MS and CFS before. They've noted similarities but also differences. The problem with ME/CFS, or CFS/ME, is that it has not been formally defined. Some studies referring to CFS/ME select patients using broad criteria for CFS. These overlap about 97% with the criteria for neurasthenia (i.e. if you meet the criteria for one, you will almost certainly meet the criteria for the other). Almost no one still studies ME as described by experts such as Dr Ramsay and others prior to 1988. Indeed, I believe that I was the last one.
It's not yet been established that ME is equivalent to CFS, so combining the two leads to the question, 'do the authors mean ME, CFS, or both, and if the latter, using which criteria?' It's not a minor issue. Many studies on CFS have found that psychological and social factors predate onset and must be considered as potential influences. In contrast, I can only recall one or two studies associating ME and post-viral fatigue syndrome with a psychological aetiology. A history of child abuse has been noted in several studies on CFS but, to my knowledge, not in ME.
ME, unlike CFS, can occur in epidemics. Studies following patients from the acute phase have found no abnormalities such as raised levels of cytokines etc, that differentiate those who recovered at six months and those who did not. Any abnormalities observed later could, therefore, be a result of variables such as the burden of illness (e.g. illness intrusiveness) or other complications.
The confusion between ME and CFS has resulted in a mountain of inconsistent findings. As CFS covers a multitude of ills, sometimes the only thing the population has in common is profound fatigue. Low NK cell activity can be a result of stress, so its clinical significance in ME/CFS needs to be established.
I welcome the immense amount of work that the authors have completed but perhaps the most important issue to be addressed, before we continue to evaluate the evidence, is to establish what we mean by ME and CFS and whether we are persuaded, given the differences identified by experts such as Prof. Jason, that they are one and the same. Only when we have tested the assumption of equivalence does it make sense to combine findings from studies on ME and CFS and compare the hybrid with diseases such as MS. In short, good science demands that we go back to basics, define terms, cast a critical eye over the findings and remain ruthlessly disapssionate.
Goudsmit, EM, Shepherd, C., Dancey, CP and Howes, S. ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychology Update, 2009, 18, 1, 26-33.
Updated: http://www.foodsmatter.com/me_and_cfs/cfs_me_causes_general/articles/goudsmit-me-clinical%20entity-10-12.html
Goudsmit, EM., Stouten, B and Howes, S. Illness intrusiveness in myalgic encephalomyelitis. An exploratory study. Journal of Health Psychology, 2009, 14, 2, 215-221.
http://hpq.sagepub.com/cgi/content/abstract/14/2/215?etoc
Competing interests
My professional judgement may be influenced by the fact that I was diagnosed with ME in the early 1980s. There is no diagnostic test for this disease but it feels like an infection and some of the lesser known symptoms are identical to those of MS. Due to the illness, I am no longer able to work as a scientist and offer readers a long list of references to support my arguments. For that, I apologise.
Goudsmit in error.
V Storey, NA
28 November 2013
I have sought the authors opinions regarding the contents of Ellen Goudsmit's comment and can now answer each point made.
The authors are grateful to Goudsmit for her interest in thier paper and they note her opinions re the nature of myalgic encephalomyelitis and methods of diagnosis so eloquently expressed in the papers she cites with interest. They always welcome the perspectives of health psychologists. The authors do however feel that many of Goudmit's comments are likely based on her misunderstanding of the contents of the paper which was targeted at expert physicians and biomedical scientists.
The authors are aware that the term Myalgic Encephalomyelitis (ME) may be used in a manner other than mandated by the WHO. This is why they have been clear that they do use the term ME in the same way as used by the WHO when referring to a disease of the central nervous system. The authors use Chronic fatigue syndrome as an alternative name for this disease of the central nervous system. Once again following WHO guidelines. They have deliberately not included studies where patients were enrolled for no other reason than they suffered from chronic weariness of an unknown origin and avoided the use of any data obtained by enrolling patients according to unpublished criteria or criteria devised by individuals holding no degrees in medical or biomedical science. The introduction of such obvious confounding variables would make any comparison between studies pointless. The authors do actually agree with the view of another psychologist Leonard Jason on that point.
The authors read Goudmits claims that no studies have examined the illness studied by Melvin Ramsey since his death with considerable astonishment. That disease was ME according to Ramsay himself. It was studied before Ramsay's great work in the field and continues to be studied by expert physicians and biomedical scientists all over the world. Indeed the recent international consensus guidelines for the diagnosis of ME constructed by such experts who have cumulatively seen 50 000 patients with this illness bears testimony to that fact.
Finally the authors do not agree with Goudsmit that the way forward is to decide what is meant by the term ME. They believe that the way forward lies with the use of science and biomarkers and the delineation of new pathways, not semantics and psychology. Clearly many people carrying a diagnosis of CFS display a range of biological abnormalities which are very similar to those displayed by people with Multiple Sclerosis. The authors believe that the way forward lies in the development of a differential diagnosis using scientific measurements which can identify people with such abnormalities and distinguish people displaying these abnormalities from people carrying the CFS diagnosis who clearly suffer from a range of illnesses of unknown or psychological origin.
Chair
NiScience
Competing interests
NA
Misunderstanding or just a different approach?
Ellen Goudsmit, NA
6 June 2014
I am disappointed with the response from the authors. If they welcome the perspectives of health psychologists, it is difficult to comprehend why they did not consider the work and views of one who has studied ME since 1982, was taught by world authorities (Drs Ramsay, Parish and Dowsett), completed a PhD on ME, and for years, summarised every published article for the British Library and the Melvin Ramsay Archive.
When it comes to interpreting the literature on a hugely complex disorder, isn't attention to detail and a critical eye more useful than a paper qualification? There are many physicians claiming to see patients with ME and CFS who adhere to simplistic explanations, attributing a myriad of symptoms to fear-avoidance and deconditionning. As science is essentially a way of analysing information, I am more than happy to work with non-scientists and laymen who have open minds and common-sense. This has led to several letters discussing flaws in the research on cognitive behaviour therapy and graded exercise which have been published in journals such as the Lancet (e.g. Stouten et al. 2011). However, if my qualification rather than my knowledge is the reason for the authors' first argument challenging my views, i.e. that I am not able to understand the contents of their paper targeted at physicians and biomedical scientists, then maybe it is worth adding that I studied at St Thomas’s Hospital in London, Leiden University Medical School, co-edited a gynaecology textbook and am a Fellow of the Royal Society of Medicine. I am familiar with biomedical research having studied the chain of events resulting in ovulation. As for competence, my peers have for many years asked me to review papers and grant applications and I used to write examination questions to help physicians pass post-graduate diplomas. I therefore believe that I am able to understand biomedical reviews on topics I have studied since 1982.
If the authors accept this and recognise that I have a lot of relevant experience, then what can I contribute to the debate? The authors wish to identify biomarkers to aid diagnosis but question my interest in increasing the homogeneity of the population and making this process easier. I focus on ME as described by experts prior to the introduction of the term CFS for a reason. Experience as well as research suggest that case definitions with a few key symptoms are potentially more accurate than those reached by consensus (e.g. Jason et al. 2012). And while the authors may have felt astonished when they read that others have not studied ME as described by Ramsay since the late 1990s, they cited no reference to support their view. Even if the assumption that the recent consensus criteria identify the same population as the criteria for ME is valid, there have been few studies using the former.
The authors' paper cited many studies appearing to support a pathological process and possible biomarker. However, the criteria used in almost all of the studies selected a population where those with a history of stress were not excluded. Moreover, the participants had to report profound fatigue for at least six months, and not as in ME, muscle fatiguability after minimal exertion plus a delay in the recovery of muscle power. This is not semantics. It's an attempt to operationalize a cardinal feature of the disease. The experts who have apparently seen 50000 patients and devised the latest consensus criteria adopted a similar approach. I was very interested in the consensus criteria but when it came to testing them for accuracy and reliability, flaws emerged (e.g. Jason et al. 2012).
While the consensus criteria are tweaked, researchers have an alternative. The first set of criteria for classic ME were devised by three expert physicians and myself in 1993. They focused on key symptoms, and although they were not published in a journal, we found that in all except one study where they were used, they tended to identify a specific abnormality in all of those tested (e.g. Costa et al. 1995; Paul et al. 1999, cf. Goudsmit and Howes et al. 2014). In other words, they appeared to select a homogeneous population as described by Drs Ramsay and Dowsett. Costa et al's finding of hypoperfusion in the brainstem is consistent with the results reported by Hyde, who found that the abnormality documented at rest increased after exercise. This and other studies indicating a close association between exertion and symptom exacerbation is the main reason why I have continued to focus on the concept of ME as described by Ramsay. Four patients, one of whom is an expert physician, collated the data on what we call classic ME and published revised criteria in 2009 (see Howes et al. 2014).
The authors have every right to follow a different path and not to differentiate between ME and CFS. However, in doing so, they are not following WHO guidelines. Those preceded a major revision of the case definition of CFS (1994). The widespread use of these criteria means that CFS is no longer distinguishable from a psychiatric disorder called neurasthenia. In short, if these individuals have raised levels of cytokines, it is possible that this is the result of psychological factors. There is growing evidence that several psychological conditions are also associated with disturbances in the HPA axis and according to Jason and others, this may affect immune function. One reason why I find research on patients selected using the 1994 criteria hard to interpret is because a significant number of participants may have been misclassified. The authors will be aware of studies linking CFS and a history of child abuse. Their inclusion could explain some of the documented abnormal cytokine levels (e.g. Danese et al. 2007). While the WHO coding and guidelines were relevant in 1993, it's a moot point whether they are appropriate now.
The authors do not have to agree with me that it’s vital to increase diagnostic precision, which explains, perhaps, why they did not identify interesting findings relating to classic ME from the studies using the unpublished criteria based on Ramsay's concept. My suggestion is that those interested in finding biomarkers might continue where many left off. There is already persuasive evidence that abnormalities in classic ME are present 24 hours after exertion (e.g. Paul et al. 1999) and I therefore propose that researchers should repeat any test to obtain reliable data. Moreover, as the illness fluctuates, the ideal study is a longitudinal one, where blood samples are taken when well-defined patients are feeling particularly ill and not only when they are well enough to attend a hospital clinic.
I submit that diagnostic clarity is essential if the authors wish to achieve their aims. And while I may have misunderstood some of their arguments, perhaps they also misunderstood some of mine?
References.
Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. PNAS, 2007; 104:1319-1324.
Jason LA, Brown A, Clyne E, Bartgis L, Evans M, Brown M. Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Evaluation & the Health Professions, 2012; 35:280-304. doi: 10.1177/0163278711424281
Stouten B, Goudsmit EM, Riley NH. The PACE trial in chronic fatigue syndrome. Lancet, 2011; 377: 1832-1833. doiI:10.1016/S0140-6736(11)60685-5
Competing interests
I was a co-author of the criteria for ME devised in 1993 and 2009.
Speculative but thought provoking
2 October 2013
As a former archivist who has read almost all publications on myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), I have come across papers linking MS and CFS before. They've noted similarities but also differences. The problem with ME/CFS, or CFS/ME, is that it has not been formally defined. Some studies referring to CFS/ME select patients using broad criteria for CFS. These overlap about 97% with the criteria for neurasthenia (i.e. if you meet the criteria for one, you will almost certainly meet the criteria for the other). Almost no one still studies ME as described by experts such as Dr Ramsay and others prior to 1988. Indeed, I believe that I was the last one.
It's not yet been established that ME is equivalent to CFS, so combining the two leads to the question, 'do the authors mean ME, CFS, or both, and if the latter, using which criteria?' It's not a minor issue. Many studies on CFS have found that psychological and social factors predate onset and must be considered as potential influences. In contrast, I can only recall one or two studies associating ME and post-viral fatigue syndrome with a psychological aetiology. A history of child abuse has been noted in several studies on CFS but, to my knowledge, not in ME.
ME, unlike CFS, can occur in epidemics. Studies following patients from the acute phase have found no abnormalities such as raised levels of cytokines etc, that differentiate those who recovered at six months and those who did not. Any abnormalities observed later could, therefore, be a result of variables such as the burden of illness (e.g. illness intrusiveness) or other complications.
The confusion between ME and CFS has resulted in a mountain of inconsistent findings. As CFS covers a multitude of ills, sometimes the only thing the population has in common is profound fatigue. Low NK cell activity can be a result of stress, so its clinical significance in ME/CFS needs to be established.
I welcome the immense amount of work that the authors have completed but perhaps the most important issue to be addressed, before we continue to evaluate the evidence, is to establish what we mean by ME and CFS and whether we are persuaded, given the differences identified by experts such as Prof. Jason, that they are one and the same. Only when we have tested the assumption of equivalence does it make sense to combine findings from studies on ME and CFS and compare the hybrid with diseases such as MS. In short, good science demands that we go back to basics, define terms, cast a critical eye over the findings and remain ruthlessly disapssionate.
Goudsmit, EM, Shepherd, C., Dancey, CP and Howes, S. ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychology Update, 2009, 18, 1, 26-33.
Updated: http://www.foodsmatter.com/me_and_cfs/cfs_me_causes_general/articles/goudsmit-me-clinical%20entity-10-12.html
Goudsmit, EM., Stouten, B and Howes, S. Illness intrusiveness in myalgic encephalomyelitis. An exploratory study. Journal of Health Psychology, 2009, 14, 2, 215-221.
http://hpq.sagepub.com/cgi/content/abstract/14/2/215?etoc
Competing interests
My professional judgement may be influenced by the fact that I was diagnosed with ME in the early 1980s. There is no diagnostic test for this disease but it feels like an infection and some of the lesser known symptoms are identical to those of MS. Due to the illness, I am no longer able to work as a scientist and offer readers a long list of references to support my arguments. For that, I apologise.
Goudsmit in error.
28 November 2013
I have sought the authors opinions regarding the contents of Ellen Goudsmit's comment and can now answer each point made.
The authors are grateful to Goudsmit for her interest in thier paper and they note her opinions re the nature of myalgic encephalomyelitis and methods of diagnosis so eloquently expressed in the papers she cites with interest. They always welcome the perspectives of health psychologists. The authors do however feel that many of Goudmit's comments are likely based on her misunderstanding of the contents of the paper which was targeted at expert physicians and biomedical scientists.
The authors are aware that the term Myalgic Encephalomyelitis (ME) may be used in a manner other than mandated by the WHO. This is why they have been clear that they do use the term ME in the same way as used by the WHO when referring to a disease of the central nervous system. The authors use Chronic fatigue syndrome as an alternative name for this disease of the central nervous system. Once again following WHO guidelines. They have deliberately not included studies where patients were enrolled for no other reason than they suffered from chronic weariness of an unknown origin and avoided the use of any data obtained by enrolling patients according to unpublished criteria or criteria devised by individuals holding no degrees in medical or biomedical science. The introduction of such obvious confounding variables would make any comparison between studies pointless. The authors do actually agree with the view of another psychologist Leonard Jason on that point.
The authors read Goudmits claims that no studies have examined the illness studied by Melvin Ramsey since his death with considerable astonishment. That disease was ME according to Ramsay himself. It was studied before Ramsay's great work in the field and continues to be studied by expert physicians and biomedical scientists all over the world. Indeed the recent international consensus guidelines for the diagnosis of ME constructed by such experts who have cumulatively seen 50 000 patients with this illness bears testimony to that fact.
Finally the authors do not agree with Goudsmit that the way forward is to decide what is meant by the term ME. They believe that the way forward lies with the use of science and biomarkers and the delineation of new pathways, not semantics and psychology. Clearly many people carrying a diagnosis of CFS display a range of biological abnormalities which are very similar to those displayed by people with Multiple Sclerosis. The authors believe that the way forward lies in the development of a differential diagnosis using scientific measurements which can identify people with such abnormalities and distinguish people displaying these abnormalities from people carrying the CFS diagnosis who clearly suffer from a range of illnesses of unknown or psychological origin.
Chair
NiScience
Competing interests
NAMisunderstanding or just a different approach?
6 June 2014
I am disappointed with the response from the authors. If they welcome the perspectives of health psychologists, it is difficult to comprehend why they did not consider the work and views of one who has studied ME since 1982, was taught by world authorities (Drs Ramsay, Parish and Dowsett), completed a PhD on ME, and for years, summarised every published article for the British Library and the Melvin Ramsay Archive.
When it comes to interpreting the literature on a hugely complex disorder, isn't attention to detail and a critical eye more useful than a paper qualification? There are many physicians claiming to see patients with ME and CFS who adhere to simplistic explanations, attributing a myriad of symptoms to fear-avoidance and deconditionning. As science is essentially a way of analysing information, I am more than happy to work with non-scientists and laymen who have open minds and common-sense. This has led to several letters discussing flaws in the research on cognitive behaviour therapy and graded exercise which have been published in journals such as the Lancet (e.g. Stouten et al. 2011). However, if my qualification rather than my knowledge is the reason for the authors' first argument challenging my views, i.e. that I am not able to understand the contents of their paper targeted at physicians and biomedical scientists, then maybe it is worth adding that I studied at St Thomas’s Hospital in London,
Leiden University Medical School, co-edited a gynaecology textbook and am a Fellow of the Royal Society of Medicine. I am familiar with biomedical research having studied the chain of events resulting in ovulation. As for competence, my peers have for many years asked me to review papers and grant applications and I used to write examination questions to help physicians pass post-graduate diplomas. I therefore believe that I am able to understand biomedical reviews on topics I have studied since 1982.
If the authors accept this and recognise that I have a lot of relevant experience, then what can I contribute to the debate? The authors wish to identify biomarkers to aid diagnosis but question my interest in increasing the homogeneity of the population and making this process easier. I focus on ME as
described by experts prior to the introduction of the term CFS for a reason. Experience as well as research suggest that case definitions with a few key symptoms are potentially more accurate than those reached by consensus (e.g. Jason et al. 2012). And while the authors may have felt astonished when they read that others have not studied ME as described by Ramsay since the late 1990s, they cited no reference to support their view. Even if the assumption that the recent consensus criteria identify the same population as the criteria for ME is valid, there have been few studies using the former.
The authors' paper cited many studies appearing to support a pathological process and possible biomarker. However, the criteria used in almost all of the studies selected a population where those with a history of stress were not excluded. Moreover, the participants had to report profound fatigue for at least six months, and not as in ME, muscle fatiguability after minimal exertion plus a delay in the recovery of muscle power. This is not semantics. It's an attempt to operationalize a cardinal feature of the disease. The experts who have apparently seen 50000 patients and devised the latest consensus criteria adopted a similar approach. I was very interested in the consensus criteria but when it came to testing them for accuracy and reliability, flaws emerged (e.g. Jason et al. 2012).
While the consensus criteria are tweaked, researchers have an alternative. The first set of criteria for classic ME were devised by three expert physicians and myself in 1993. They focused on key symptoms, and although they were not published in a journal, we found that in all except one study where they were
used, they tended to identify a specific abnormality in all of those tested (e.g. Costa et al. 1995; Paul et al. 1999, cf. Goudsmit and Howes et al. 2014). In other words, they appeared to select a homogeneous population as described by Drs Ramsay and Dowsett. Costa et al's finding of hypoperfusion in the brainstem is consistent with the results reported by Hyde, who found that the abnormality documented at rest increased after exercise. This and other studies indicating a close association between exertion and symptom exacerbation is the main reason why I have continued to focus on the concept of ME as described by Ramsay. Four patients, one of whom is an expert physician, collated the data on what we call classic ME and published revised criteria in 2009 (see Howes et al. 2014).
The authors have every right to follow a different path and not to differentiate between ME and CFS. However, in doing so, they are not following WHO guidelines. Those preceded a major revision of the case definition of CFS (1994). The widespread use of these criteria means that CFS is no longer distinguishable from a psychiatric disorder called neurasthenia. In short, if these individuals have raised levels of cytokines, it is possible that this is the result of psychological factors. There is growing evidence that several psychological conditions are also associated with disturbances in the HPA axis and according to Jason and others, this may affect immune function. One reason why I find research on patients selected using the 1994 criteria hard to interpret is because a significant number of participants may have been misclassified. The authors will be aware of studies linking CFS and a history of child abuse. Their inclusion could explain some of the documented abnormal cytokine levels (e.g. Danese et al. 2007). While the WHO coding and guidelines were relevant in 1993, it's a moot point whether they are appropriate now.
The authors do not have to agree with me that it’s vital to increase diagnostic precision, which explains, perhaps, why they did not identify interesting findings relating to classic ME from the studies using the
unpublished criteria based on Ramsay's concept. My suggestion is that those interested in finding biomarkers might continue where many left off. There is already persuasive evidence that abnormalities
in classic ME are present 24 hours after exertion (e.g. Paul et al. 1999) and I therefore propose that researchers should repeat any test to obtain reliable data. Moreover, as the illness fluctuates, the
ideal study is a longitudinal one, where blood samples are taken when well-defined patients are feeling particularly ill and not only when they are well enough to attend a hospital clinic.
I submit that diagnostic clarity is essential if the authors wish to achieve their aims. And while I may have misunderstood some of their arguments, perhaps they also misunderstood some of mine?
References.Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. PNAS, 2007; 104:1319-1324.
Goudsmit, EM. Articles on ME. http://www.foodsmatter.com/me_and_cfs/cfs_me_causes_general/index_cfs_causes_general.html
Howes S, Goudsmit E, Shepherd C. Myalgic encephalomyelitis (ME). Criteria and clinical guidelines 2014. Available from: http://www.axfordsabode.org.uk/me/mecrit2014.htm
Jason LA, Brown A, Clyne E, Bartgis L, Evans M, Brown M. Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Evaluation & the Health Professions, 2012; 35:280-304. doi:
10.1177/0163278711424281
Stouten B, Goudsmit EM, Riley NH. The PACE trial in chronic fatigue syndrome. Lancet, 2011; 377: 1832-1833. doiI:10.1016/S0140-6736(11)60685-5
Competing interests
I was a co-author of the criteria for ME devised in 1993 and 2009.