Articles

179 thoughts on “Rituximab for Chronic Fatigue Syndrome: Jumping the Gun

  1. pmoran says:

    “Unmet medical need/desire” + something of marginal or nonexistent plausibility promoted as helping + [brave maverick doctor or charlatan] – proper informed consent = considerable use of [unproven or disproven] treatments

    Commendable effort, David!

    However, among other things, you don’t need the ongoing presence of a “[brave maverick doctor or charlatan]“. The vast majority of CAM use is enabled or triggered by either personal testimonial or the advice of laymen or other sufferers.

    Line up all the quacks and shoot them, as per our oft-time mutual inclinations :-), and patients and enthusiastic amateurs would simply carry on, sifting through medical history, the writings of Hulda Clark, Pauling, Revici, Gerson and whomever, and also the published medical literature for treatments to try out.

    Very often also it is mainstream research, or a misreading of it, that stirs up “CAM” use. What doesn’t affect cancer in tissue culture, for example? Look at all those positive studies of glucosamine. It also requires some scientific gymnastics and niceties to completely dispose of the “positive” studies for treatment programs based upon acupuncture. Who can blame patients with difficult problems like chronic pain for wanting to try out methods that at least at first sight our own research seems to support?

    See this, for example –

    http://archinte.jamanetwork.com/article.aspx?articleid=1357513

  2. geo says:

    “the same principle applies because we know so little about CFS that it is impossible even to estimate the plausibility. When we don’t know, the conservative and safe default is to assume it’s implausible until there is some good positive evidence to support its plausibility.”

    Doesn’t that mean that no doctors would be allowed to provide ‘treatment’ for CFS outside of trials?

    If this approach had been taken over the last 25 years, I think that we would now be in a much better place.

    @mousethatroared:

    “Yup, those discussions are not my favorite, either. :) And it’s hard to find a blog that focuses on real nuanced discussions on skepticism in clinical psychology, a shame.”

    Unfortunately, checking citations, trawling through data and explaining why certain statistical tricks are misleading doesn’t seem to make for the sort of easy reading people want for blogs. I’m guilty here too, as while I respect and read Coyne’s posts, I really don’t give them the attention and follow-up reading that they deserve. For something like CFS, where it’s harder to meaningfully measure outcomes, there’s little high quality research, and already a lot of animosity and distrust, it’s even less likely people would be willing to do this sort of work.

  3. WilliamLawrenceUtridge says:

    If you know something about the pathophysiology of CFS that indicates that ritux is implausible or marginally plausible as a treatment, please share it.

    If you know anything about the pathophysiology of CFS, please share it! I was under the impression that there is still no well-accepted, well-validated etiology or pathophyisiology of CFS. How can we assume rituximab has any prior probability when you don’t know the cause? It’s like hypothesizing about the architecture of the alien civilizations on Alpha Centauri Bb. Certainly, given evidence supporting CBT and GET (problematic though it is) gives more prior plausibility to antidepressants than rituximab. CFS payments may find this objectionable, but science is about generating correct knowledge, not preserving feelings.

    Also, if you have any substantive evidence that Dr. Kogelnik is “a brave maverick doctor” (your link implied a comparison with Andrew Wakefield) or a charlatan, please share that, too. The Open Medicine website’s use of buzzwords that you don’t like doesn’t count. It’s not directed at you.

    The comparison to Wakefield, whose motivation was probably in part greed, might not be apt – but there are also doctors motivated by a sincere desire to help patients that pushes them down the path of pathological science. Buzzwords are indeed part and parcel of actively fraudulent doctors as well since they can’t explain their treatments to their peers with real science and evidence.

  4. irenef says:

    @PernilleN:

    Yes, it’s too bad that rituximab costs so much and that airfare is so expensive. People here travel to foreign countries for medical care, too, and it costs money.

    In this country we have a tradition of allowing people to make their own decisions about how to run their lives.

    As far as Fluge and Mella–the Norwegian researchers–they are signatories to the Open Medicine Institute’s research initiative:

    http://openmedicineinstitute.org/research-initiatives/mecfs-merit/

    I was never led to believe there was a close relationship, other than that they are in contact. I would assume they know OMI is treating patients with ritux. But I don’t see how they have any rights to contol its usage.

    “I must say Kogelnik has a lot of nerve going against their advice. I’m sure he means well and wants to help, but what he is doing is still wrong.”

    I think you have a lot of nerve by making these accusations. I’m sure you mean well and want to help, but what you are doing is still wrong.

  5. Harriet Hall says:

    Pernille reported that Fluge and Mella “have said very clearly that the drug should not be used outside clinical studies. ”

    Of course they don’t “have any rights to control its usage” and no one ever suggested that they do. A bit of an over-reaction on your part, don’t you think? They did have the right to offer their advice, based on their interpretation of the evidence from their own studies. Kogelnik is going against that advice. Pernille offered her opinion that what he is doing is wrong. I agree. That’s what I said even before I was aware of Fluge and Mella’s specific advice.

    I don’t think that indicates she “has a lot of nerve to make these accusations.” Now you have offered your opinion that Pernille’s offering her opinion is wrong. What are we to make of that?

  6. irenef says:

    @WilliamLawrenceUtridge:

    I’ve already given a quite brief explanation of the rationale for the use of ritux and a citation about its pathophysiology. I realize this is in no way adequate but I’m really not the person to ask. It takes me a long time to respond and I have some other things to do. I’m lucky that I have the energy and focus to do anything.

    I also suffer from major depressive disorder. Is there a well-accepted, well-documented etiology for that? I’ve taken a gamut of drugs running from Ativan to Zyprexa, including lithium, and received ECT. What about an explanation of how those things work? My treatment was essentially a series of throws to see what would stick, until something finally did. It took decades. Does anyone know about the long-term consequences of those drugs?

    CBT? Don’t make me laugh.

    In truth, all this fuss over unknown dangers and unknown effects and about physician responsibility and informed consent leaves me a little cold. The real world is quite a bit messier.

  7. Sialis says:

    @irenef, May I ask, do you have a history of trauma, emotional or physical, either a single extreme incident or sustained abuse or neglect over a length of time?

  8. irenef says:

    @Harriet Hall:

    Your objection to the interview revolves around a single clause involving semantic niceties that would not be meaningful to most people who watch the video. Dr. K also urges caution and says that the drugs are not to be used lightly.

    I think Pernille is unduly concerned about what *other* people do and how they spend their own money. People have a tendency to do things we don’t like, but there are limits to the degree to which we can legitimately interfere, and I think both you and Pernille are wrong in making accusations of unethical and irresponsible behavior for which you have little more than hearsay evidence.

  9. Harriet Hall says:

    If the evidence we have is hearsay and is wrong, Dr. Kogelnik is welcome to join the comment thread and set the record straight. Apart from the apparent miscommunication (whether his fault or the fault of others), it now seems abundantly clear that he is treating patients outside clinical trials. That is not illegal and there is room for a difference of opinion. I doubt if a medical board would classify it as unethical, but I have explained why in my opinion I consider it not to be in the best interests of all patients in the long run.

  10. David Gorski says:

    However, among other things, you don’t need the ongoing presence of a “[brave maverick doctor or charlatan]“. The vast majority of CAM use is enabled or triggered by either personal testimonial or the advice of laymen or other sufferers.

    Without the brave maverick doctor or quack, the patient has no way to get the unproven medicine.

  11. Sialis says:

    As for the Norwegian doctors who discovered that Rituximab may be useful for some ME patients: They have said very clearly that the drug should not be used outside clinical studies.

    @irenef, Did your doctor, Dr. K tell you that the Norwegian doctors who discovered that Rituximab may be useful for some ME patients also make it very clear to you that they said the drug should not be used outside of clinical trials, and did Dr. K explain in detail why this should be?

    If he didn’t, then he is experimenting on you without providing you all of the relevant information so you can make an informed decision. He is misleading you. Lots of maverick doctors seem to misrepresent the initial research findings of others in this way – it gets patients in their offices who are desperate and willing to pay for expensive ‘cutting-edge’ treatments. Treatments, which have shown little evidence of efficacy and pose great risk to the patient, and mostly serve to line the pockets of the doctors and gain publicity for their practices among the ill and the desperate, thus bringing in more patients. In my opinion, it is the very definition of unethical and irresponsible medical care.

  12. David Gorski says:

    I doubt if a medical board would classify it as unethical, but I have explained why in my opinion I consider it not to be in the best interests of all patients in the long run.

    It’s certainly skirting the edge of unethical behavior and possibly going over.

  13. irenef says:

    @Sialis:

    No, no history of trauma, abuse, or neglect.

    Children raised in bad circumstances seem to have poorer outcomes overall, but I don’t think there’s any direct link to CFS, despite what the CDC has claimed. I don’t it was a good study.

    But let’s not open that particular can of worms.

    I just happen to have both MDD and CFS. The double whammy.

  14. Sialis says:

    The vast majority of CAM use is enabled or triggered by either personal testimonial or the advice of laymen or other sufferers.

    Do you think that most patients merely wake up one day and decide on their own to write a testimonial without any encouragement from the physician, their staff or their attorneys? Those testimonials serve to both advertise and gain protection for the doctor. I sincerely doubt that they are all whim decisions, letters of support written without any other hidden agenda. Certainly not in my experience.

  15. Sialis says:

    @irenef, there was an announcement made by the FDA recently that they are changing the dosage guidelines for Ambien when used by women. They are now recommending half the dosage, as too many women apparently have slower metabolism of the drug. It is causing them to be over-medicated the next day. Sometimes doctors overlook the fact that the medications they prescribe could be causing some of their patients disabling symptoms. It seems to me that providers sometimes focus on what else is happening to a patient, rather than consider that their care, or lack thereof, could be the source of the problem.

  16. irenef says:

    @Sialis:

    I don’t get the CAM quote. It didn’t come from me.

    Are you insinuating that someone else is putting words into my mouth? You are wrong.

    But I suppose I should be complimented in a way, because that means you think li’l old me couldn’t possibly have sufficient mental horsepower to say what I’ve said.

    Ambien? I don’t take Ambien. I’ve experienced side effects from a drug that were overlooked by my physician. It was one of the reasons that I quit going to him.

    Maybe I don’t have sufficient mental horsepower, because I feel like you’re expressing a concern that I’m not grasping.

  17. CumGranoSalis says:

    @ David Gorski

    “Without the brave maverick doctor or quack, the patient has no way to get the unproven medicine.”

    This is absolutely not true. Rituximab may be pretty hard, or even impossible, to acquire and administer if a patient decides to self-medicate. However, many other drugs (antidepressant, anti(retro)virals, PDE-5 inhibitors, performance enhancing drugs etc. etc.) are easily obtainable through overseas pharmacies.

    I just read a paper* about a 15 year old patient with anti-NMDA receptor encephalitis being treated with rituximab. There are couple more of these case reports and in this condition there are also no published and/or registred (pilot) trials. Is this also considered unethical and if not, why not?

    * http://ajp.psychiatryonline.org/article.aspx?articleid=1555615

  18. nybgrus says:

    Sometimes doctors overlook the fact that the medications they prescribe could be causing some of their patients disabling symptoms

    A decent chunk of the practice questions for my next round of board exams focuses on this issue. They set up a scenario in which something is wrong with the patient and ask you what the next best investigation is. The answer is “check for drug interactions or side effects.” From my perspective in studying for the boards, this seems to be harped on quite a lot actually. They don’t care that you know specifically which drug it is or what the interactions or side effects are, just that you should be looking for them. I think this is very good, since any idiot with a smart phone can pull up epocrates to check the interactions and side effects. But you need to think to take the phone out of your pocket in the first place.

  19. Sialis says:

    Maybe I don’t have sufficient mental horsepower, because I feel like you’re expressing a concern that I’m not grasping.

    @irenef: That quote was from someone other than you. I should have put their name in my comment. My other point, though not well made, was that sometimes patient’s symptoms are a result of their medical interventions, either the medications they are prescribed, or other medical treatments. I think those things are too readily dismissed by some physicians, perhaps especially those with larger egos. My assumption is that oftentimes those with chronic illness are on multiple medications. This in itself would pose a greater risk of drug interactions and more risk of side effects and adverse reactions. I don’t want to ask you what medications you are taking and I certainly wouldn’t expect you to post that online, nor am I licensed to offer an opinion on them. A lot of the symptoms you listed could be caused or exacerbated by various medications. I just urge you to examine them carefully and perhaps get a second opinion from a physician who is not associated with your current one – what about nybgrus? He sounds like a keeper to me. Get some sleep, dear.

    @nybgrus, I think there’s more to it than remembering to look things up on epocrates, although that is indeed a good start. Look it up in front of the patient so they know that you care. It seems that sometimes the problem resides with the physician being able to admit that their patient, the one they are medicating is indeed experiencing an adverse reaction to the medications they prescribed. Some physicians sometimes have difficulty recognizing and/or admitting to their own prescribing errors, and seem under an outright gag order when it comes to speaking negatively about what another physician may be doing to a shared patient. Patients should be told straight up, “Your doc is a quack, and it’s specifically because of this and that”, instead they are likely told “You may want to think about getting another opinion sometime.” I also think some physicians have a hard time admitting to their mistakes, and as a result they take little action to correct them, mostly because they fear looking stupid or possibly being sued for the medical mistake.

  20. irenef says:

    @sialis:

    Thank you for your concern. Drug interactions and side effects are something I think about because I’ve experienced them.

    Nybgrus sounds like a nice fellow, reasonably intelligent, too. (I think he’s male, isn’t he?). I wonder if he wants to live in San Francisco.

    I’ll be awake for another five or six hours. The night is young.

  21. pmoran says:

    “The vast majority of CAM use is enabled or triggered by either personal testimonial or the advice of laymen or other sufferers.”

    Do you think that most patients merely wake up one day and decide on their own to write a testimonial without any encouragement from the physician, their staff or their attorneys?

    Yes. For all I know some of those on promotional web sites may have been solicited, but there are plenty of others on blogs, mailing lists and newsgroups.

  22. nybgrus says:

    I think there’s more to it than remembering to look things up on epocrates, although that is indeed a good start. Look it up in front of the patient so they know that you care. It seems that sometimes the problem resides with the physician being able to admit that their patient, the one they are medicating is indeed experiencing an adverse reaction to the medications they prescribed. Some physicians sometimes have difficulty recognizing and/or admitting to their own prescribing errors, and seem under an outright gag order when it comes to speaking negatively about what another physician may be doing to a shared patient. Patients should be told straight up, “Your doc is a quack, and it’s specifically because of this and that”, instead they are likely told “You may want to think about getting another opinion sometime.” I also think some physicians have a hard time admitting to their mistakes, and as a result they take little action to correct them, mostly because they fear looking stupid or possibly being sued for the medical mistake.

    Of course. I didn’t mean my comment to completely describe the situation.

    And the whole “admitting errors” with patients is a big thing. Part of the ethics talk I will be giving to the new 3rd Year students as part of their orientation. I’ve been tasked with chatting about the new medical ethics resource and research project the hospital is doing and to encourage students to participate. I think it is a good idea, and I think we should always admit our error and admit when we don’t know something. This is an intentional and concerted effort on the part of both undergraduate and graduate medical education with mandatory training in systems models, ethics, and professional practice. Unfortunately there will always be those who blow it off or think it is stupid. But I think those are a fading minority and the culture shift of open communication and teamwork is well underway, which will put a lot of pressure on those of my colleagues who aren’t as considerate in these regards.

    I can also speak anecdotally that many in my med school, and particularly the friends I keep, are very like minded. We plan on making our student society reflect these ideals which includes academic rigor as well.

  23. nybgrus says:

    Nybgrus sounds like a nice fellow, reasonably intelligent, too. (I think he’s male, isn’t he?). I wonder if he wants to live in San Francisco

    I am a he. And thank you for the kind words.

    San Fran is a possibility, though less likely. Not as much aerospace industry there for my significant other to pursue her career. Southern California is our long term goal, but Harvard/MIT is also on the radar for us.

    We may also stay where we are for a bit as well.

    Hopefully you will get some rest. I am off to bed shortly myself.

  24. marti says:

    Harriet Hall said

    “It has certainly not been established that CFS
    symptoms can be attributed to B cell abnormalities ”

    Have you read this paper, Altered fictional B-cell subset populations in patients with CFS compared to healthy controls
    A.S.Bradley
    B.Ford
    A.S.Bansal

    http://onlinelibrary. wiley.com/doi/10.1111/cei.12043/abstract

  25. nybgrus says:

    I don’t have institutional access to that journal so all I could read is the abstract, however this does not establish that CFS can be attributed to B cell abnormalities.

    The study was small (33 CFS and 24 health controls) and noted a few differences in B cell sub population proportions between the two groups. The authors themselves do not know know the significany (i.e. if there was literature to support a tentative hypothesis as to what this means or why, they probably would have mentioned it).

    It is a curious hypothesis generating study but nothing more. Larger studies need to be done to verify the findings of this one. It does not justify the experimentation of ritux with CFS in any manner (from a purely scientific prior plausibility standard) let alone as off label use.

  26. irenef says:

    You can contribute toward the larger studies that everyone agrees are essential:

    http://openmedicineinstitute.org/foundation/mission/

  27. nybgrus says:

    Invest in accelerating collaborative medical research to find effective treatments and diagnostic markers for neuro-immune diseases including: ME/CFS, Autism, MS, Lyme and others

    I’m pretty sure there is no evidence that Lyme disease is a neuro-immune disease (save the already well described neurological sequelae such as Bell’s palsy). This seems suspicious of the “chronic Lyme” syndrome which has been discussed here at SBM numerous times.

  28. irenef says:

    @nybgrus:

    Beats me. I know very little about Lyme. We were discussing CFS.

  29. nybgrus says:

    @irenef:

    It was a critique in that chronic Lyme is a “brave maverick doctor” diagnosis that has no supporting evidence and plenty against it. The inclusion in the list on the mission statement of OMI is a red flag in my skeptical mind.

  30. irenef says:

    @nybgrus:

    You could be right. As I mentioned before, I don’t care for the website. It hasn’t been up very long. Further discussion of it just seems like a tangential discussion that would yield more heat than light.

  31. nybgrus says:

    @irenef:

    Indeed. A red flag doesn’t mean anything by itself. Smoke usually means fire but not always. But in context of the post here, it seems relevant.

  32. marti says:

    From the paper

    “‘Over the last decade we have observed an elevated prevalence of persistent fatigue in our patients with primary antibody deficiency and speculated on subtle B cell dysfunction.”

    Importantly, Rituximab does not simply deplete CD20+ cells (B-cells) but has many mechanisms, including down regulating CD40L and GR80 on B -cells, decreasing CD4 effactor cells ,reducing NK cell numbers and activation, including macrophage maturation and reducig TNF alptha secretion and increasing the suppressive function of T regulatory cells [11]. However, the onset of B -B-cell depletion did correlate with reduction in symptoms and with the expected appropriate lag phase.

    So it might be more involved than simply depleting B-cells, though that seems to be,an important aspect.

    “Defective antibody class switching and antibody production would result in recurrent infection as seen in primary immunodeficiency states; however a milder defect may lead to inappropriate immune response and possibly autoimmunity”.

    Suggesting that autoimmunity may be a milder result on a spectrum that also includes immune deficiency.

    “Thus CFS patients may have some unusual, unrecognized autoimmune disease, or it is possible that CFS patients are unable to control lymphotrophic viral infection due to some defect of B-cell memory or T-cell dysfunction”.

    Also talks about auto-reactions B-cells usually getting destroyed when they are made and speculate the we might have a problem with that destructive process

    B cells can become either follicular B cells or marginal zone B-cells. Follicular B-cells might become plasmablasts of memory B cells, but the marginal zone B-cells always become plasmablasts

    “One explanation for reduced plasmablasts in the CFS cohort is that increased numbers of transitional B-cells and naive B-cells may overwhelm the B-cell maturation process, which may consequently become suboptimal. Alternatively T-cell help provided by cytokines may not support naive B cells to develop into plasmablasts”.

    They are interested in studying the B-cells before and after Rituximab use, to see how that alters B cell populations
    . They are also interested in whether severe patients have more extreme results since they were just studying moderate cases where some immune symptoms were only intermittent.

    “In conclusion we have observed patients with moderate CFS to have increased proportion of transitional and naive B-cells and reduced
    plasmablasts. The precise basis for these findings is unclear and our work does not allow clarification of whether these changes are cause of the CFS symptoms or the result of patient inactivity
    , sleep disturbance or raised stress, therapeutic response to Rituximab suggests that B-cells are some how involved in the pathogenesis or perpetuation of CFS symptoms”

  33. Harriet Hall says:

    “The precise basis for these findings is unclear and our work does not allow clarification of whether these changes are cause of the CFS symptoms or the result of patient inactivity, sleep disturbance or raised stress…”

    Our point exactly! The research “does not establish that CFS can be attributed to B cell abnormalities.”

  34. Hip says:

    Dear Harriet

    It is in fact quite common for doctors who specialize in treating ME/CFS patients to take an experimental approach.

    This is because it is the unfortunate case that most scientists find research into ME/CFS just plain boring and unsexy, and as a consequence, the whole field is underfunded and neglected. So to an extent, this shifts the task of ME/CFS research and experimentation to clinicians.

    Very few scientists ever dedicate their careers to studying ME/CFS. Even my own primary care doctor intimated to me that “nobody in the medical profession seems at all interested in ME/CFS”. I am an ME/CFS patient myself, incidentally.

    Perhaps you might consider writing a new article specifically examining why scientists on the whole find research into ME/CFS boring, and why so few talented minds go into this field. This is the crux of the problem ; it is why there are no real treatment advancements for this life-robbing disease.

    I actually had an idea about writing a booklet summarizing the fascinating mental and neurological aspects of ME/CFS, written in such a way as to demonstrate that ME/CFS is a deeply intriguing phenomenon.

    My idea is that if you present the fascinating facets of ME/CFS in a way that engages the imagination of scientists, you might start getting more talented researchers dedicating their energies into unravelling the mysteries of ME/CFS.

    Just a few of the fascinating facets of ME/CFS are as follows:

    One particularly intriguing phenomenon is the significant overall lowering of consciousness and dulling of awareness you experience as a patient with ME/CFS. This reduced consciousness is called cognitive dysfunction, or more colloquially, “brain fog”. Brain fog makes you do all sorts of funny things. One ME/CFS patient I know actually forgot her own name when she was asked for it, due to brain fog, and had to get her husband to tell her what it was! Why does this brain fog occur in ME/CFS? Nobody really knows. Too few people have investigated it.

    As a postgraduate, I actually studied cognitive science before I developed ME/CFS (from a respiratory virus), and during my studies I was particularly interested in the nature of consciousness. It seems to me that a disease like ME/CFS, in which there is a dulling or weakening in consciousness, might be a useful area of study for furthering the understanding of the phenomenon of consciousness.

    Another intriguing symptomatic aspect of ME/CFS is the loss of the ability of the brain to filter out irrelevant or repetitive stimuli. In a normal healthy person, if for example they hear a car alarm go off down their street, at first this new noise rouses their consciousness attention, but then they soon forget about it, and after a few minutes, it does not really enter consciousness anymore. The technical name for this filtering out of repetitive stimuli is called habituation. Habituation acts to filter out repetitive stimuli, in order to prevent overloading of consciousness awareness with irrelevant information. In ME/CFS, repetitive noises such as car alarms can be extremely aggravating, because the brain is no longer able to properly habituate to repetitive noises, and so the noise is not filtered out, and thus deeply impacts into consciousness, becoming highly unpleasant an intrusive. Why does this happen in ME/CFS? Nobody really knows.

    I also find it fascinating that language skills are significantly hit in ME/CFS patients. People with ME/CFS often develop “tip-of-the-tongue” word recall problems, grammatical problems, decreased spelling abilities, loss of vocabulary, and so forth. Why is language affected in this way? Nobody really knows.

    And of course a defining characteristic of ME/CFS is the intriguing phenomenon where physical or mental exercise will quickly and dramatically worsen all ME/CFS symptoms. Why does this happen? Nobody really knows.

    So in fact ME/CFS presents a fascinating array of strange symptoms. I cannot really understand why talented medical researchers choose not dedicate their careers to studying ME/CFS.

    Perhaps you will take up my challenge of writing an article that tries to throw more light on why this is the case.

  35. Harriet Hall says:

    “I cannot really understand why talented medical researchers choose not dedicate their careers to studying ME/CFS.”

    I can. It’s a controversial area, there is no test for CFS, it’s difficult to pin down who has it and what to study, there are more promising ways to spend research time and money, it’s perceived as a career-buster, discussion of CFS is overrun with emotion, etc. etc. Some medical researchers “have” dedicated their careers to studying CFS, with disappointing results. Edward Shorter’s book “From Paralysis to Fatigue” and “Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome” by Hillary Johnson shed a lot of light on the subject. The history of medicine is full of diseases with changing names that all involve “a fascinating array of strange symptoms,” and many of those symptom complexes have come and gone according to societal perceptions (“fads”). It would probably make more sense to study that spectrum, in the light of history, rather than just what is currently designated CFS. My personal guess is that we will eventually learn that a few patients with an objective disease are being lumped together with a lot of people who have somatoform disorders and psychological problems. Until that can be sorted out, research just adds to the confusion.

  36. mousethatroared says:

    HH “My personal guess is that we will eventually learn that a few patients with an objective disease are being lumped together with a lot of people who have somatoform disorders and psychological problems. Until that can be sorted out, research just adds to the confusion.”

    How can you sort it out without research?

    As to cognitive dysfunction or “brain fog” – This is also a feature in some diseases and processes, Thyroid disease, Lupus and other systemic autoimmune diseases, menopause, anxiety and depression are the one’s I know off the top of my head. From my reading (which is limited to a laymen’s understanding) it doesn’t seem well understood in any of these cases. Bummer.

  37. Janet says:

    @ Yikes, I must read more thoroughly. Thanks for the note way up there that Retuximab is an accepted RA treatment. I read this blog early in the morning at the start of the coffee ritual and I’m not sure my brain is fully awake.

  38. Harriet Hall says:

    “How can you sort it out without research?”

    First you need to do the necessary research to find out if CFS really exists as a definable entity. Current research jumps the gun, accepts the diagnosis, and goes on from there.

    “brain fog” is undefined. Anyone who doesn’t feel well or is depressed can experience it. Tests for cognitive dysfunction are problematic because they are effort-dependent. If you aren’t motivated to try as hard, you don’t test as well. And many CFS patients are defensive and want to prove they are objectively sick. Not to say it can’t be studied, but studies will require very careful methodology to rule out all the confounders.

  39. PernilleN says:

    @IreneF wrote: “I think Pernille is unduly concerned about what *other* people do and how they spend their own money.”

    One of the reasons SBM exists, is that many people spend a lot of money for useless and/or dangerous treatments, whether the treatments are provided by well-meaning CAM practitioners, doctors, nurses or not-so-well-meaning charlatans. The doctors who write this blog are concerned both about misrepresentation and misinformation of medicine and science, and about sick people who buy into useless and/or dangerous treatments.

    Do you also think their concern is “undue”?

    Re Fluge and Mellas advice (which they have said publicly, I don’t know what they’ve said to Kogelnik, if anything), and the fact that Kogelnik goes against that advice … what kind of accusation have I made? I said he has a lot of nerve, and that I think what he’s doing is wrong. That’s an opinion, not an accusation.

    I thought people in your country believe in freedom of speech?

    About people here having opinions based on hearsay: If OMI were open about their research and practice, and it was possible to find information on their website, we didn’t need to speculate. But they don’t. There’s no information about ongoing projects or treatments, they haven’t registered their projects in clinicaltrials.gov so we could see their protocols, and the information given in the Youtube videos is at best vague. I must confess I haven’t seen all of them, I want to read about research project, not watch them on TV. But judging from what other people say, there’s not much specific information to be found there.

    Regards
    Pernille Nylehn

  40. Sialis says:

    It would probably make more sense to study that spectrum, …

    Dr. Hall and others, given the absence of effective treatments and definitive diagnostic tests, and while more defined medical studies are on-going, what are your thoughts on having diagnostic and treatment centers that are organized in a roundtable fashion where the patient would meet with specialists from several different fields simultaneously for their initial evaluation and periodic follow-ups? One physician in the group would be assigned as the primary care provider, and oversee their treatments, but otherwise, the patient would be seen by a panel of appropriate specialists. For example, a patient with chronic, disabling symptoms diagnosed as CFS or FMS might have diagnostic/treatment interviews with a panel consisting of a neurologist, rheumatologist, infectious disease, pain management, allergy/immunologist, physical therapist, psychologist, and pharmacologist, with one of them being assigned as the primary care provider.

    In my experience, despite their training and experience, many physicians do indeed overlook or misdiagnose various symptoms. They do indeed dismiss valid symptoms of disease or effects of medications as mental health problems. I feel this is especially true for female patients, unfortunately, but I could be biased with this thought. The misdiagnoses and oversights are understandable in many cases, as physicians are only human and they’re likely overworked, short on time and unable to devote enough follow-up time as is needed for the more time/resource-consuming, chronically ill patient.

    I’ve too often seen where a classic symptom(s) is overlooked by what should have been the appropriate expert, and is instead realized much later by the patient or another physician of another area of expertise. It seems to me it would be helpful if everyone were in the same room at the same time and looking at the same things (the patient and a complete set of records and films). The physicians would all hear the same description of the symptoms from the patient, they could each ask questions and all hear the responses, and thus engage in meaningful roundtable discussion of the possible causes and treatments.

    In the above scenario, if various specialists requested testing or other assessments, those tests could be ordered by the primary care provider, who would distribute the results to each panel member for review prior to the next roundtable follow-up appointment. It seems to me that better communication amongst providers would eliminate a lot of miscommunication, misdiagnoses, unnecessary testing, and careless and unnecessary prescribing, which all too often happens, in my experience.

    1. Harriet Hall says:

      @sialis,

      A multidisciplinary team is ideal for many conditions, especially chronic pain; but applying the concept to CFS might be problematic. It would serve to rule out other diagnoses, pick up on other conditions that could be treated, etc. But it might result in unnecessary tests being ordered (each specialist would have his favorite things to pursue) and it might increase the patient’s conviction that something is objectively wrong that is still being missed. There is something to be said for a single physician to gain the patient’s trust, do reasonable rule-out tests and when nothing is found, reassure the patient and enlist the patient’s cooperation in useful therapies like exercise and psychotherapy. With the present state of medical knowledge, instead of going on a wild goose chase for an elusive explanation, it probably makes more sense to accept that we just don’t know and to concentrate on helping the patient live with the illness and build strengths to cope and improve quality of life. While keeping an open mind, of course.

      This is actually a common situation in primary care. For a patient with irritable bowel syndrome (IBS), I might tell him we couldn’t find anything structurally wrong with his bowel, but bowel functioning that is within the normal range seems to sometimes cause distressing symptoms for some people who are unusually sensitive or reactive. I might tell him we had done all the reasonable tests to rule out serious life-threatening causes and any further testing would be only likely to do more harm than good (for instance, we could do exploratory surgery and look around in his abdomen, but that is risky, unpleasant, and very unlikely to change our plan of management). I might praise the coping skills he was already using. I might tell him medical science couldn’t cure his problem, but it could do a lot to help him live with it. I could offer him understanding, sympathy, and support. And I would stress that we would be constantly monitoring new research and would quickly respond if any new symptoms developed (or changes in old symptoms) that might mean the situation had changed and that further testing was now indicated.

      I’ve written a couple of articles on related subjects:

      http://www.sciencebasedmedicine.org/index.php/not-treating-a-neglected-option/
      http://www.sciencebasedmedicine.org/index.php/overdiagnosis/

  41. mousethatroared says:

    Sialis – I’m not sure if you are aware of this, but your suggestion is similar to the Cleft Clinic model recommended for all children with Cleft Lip and Palate. My son has an annual appointment were he is examined by the Plastic Surgeon, Audiology, Pediatric Neuropsychologist , Speech Therapy, Nutrition Expert (I always forget the title), Reps from Maxillofacial Surgery, dentistry and orthodontics. The team has a group of patients for each clinic day and then goes through all the records in the afternoon and hashes out all the recommendations so that the applicable specialists are in agreement. It’s great. I will say that there is not alot of unnecessary prescribing for CLCP (that I know of) but clearly unnecessary or poorly timed surgery, therapies or dental/orthodontics are concerns that this model deals with. So maybe there is enough similarity to use that plan as a model.

  42. mousethatroared says:

    As an aside, we don’t get a round table discussion with the Cleft Clinic, but we do get a report after the clinic with the recommendations from the team, signed off on by the whole team.

  43. Hip says:

    Science-Based Medicine » Rituximab for Chronic Fatigue Syndrome: Jumping the Gun

    Quoting Harriet: “It’s a controversial area, there is no test for CFS, it’s difficult to pin down who has it and what to study, there are more promising ways to spend research time and money, it’s perceived as a career-buster, discussion of CFS is overrun with emotion, etc.”

    Yes, this is all true, and I can see how these background circumstances of ME/CFS could discourage the average scientist, or a scientist who sees his profession not as a vocation, but merely as a job. However for a scientist with idealism and talent, that should not be an insurmountable problem. Brilliant minds are often more motivated by intense scientific curiosity of their chosen area, rather than career realpolitik. I still suspect that the main reason researchers avoid ME/CFS is that many find the field boring, for some reason or another.

    Though given that you do appreciate the difficulties of attracting anyone to work in the ME/CFS research field Harriet, shouldn’t your views on experimental clinicians like Dr Andreas Kogelnik be little less critical? Or even to a degree understandingly supportive? In ME/CFS, there are often no other avenues of treatment research outside the efforts made by these ME/CFS clinicians. Imperfect I know, but it is all there is.

    Quoting Harriet: “My personal guess is that we will eventually learn that a few patients with an objective disease are being lumped together with a lot of people who have somatoform disorders and psychological problems. Until that can be sorted out, research just adds to the confusion.”

    You talk of somatoform disorders as if they were an evidenced-based, scientific concept. Perhaps your skills in identifying scientific fallacies and logically flawed concepts is not quite up to scratch?

    The flawed foundations of the somatoform disorder concept are based on the idea that if you cannot find a physical cause for a disease, then the disease may be somatoform. Yet there is no way to positively prove that a disease is somatoform; or even prove that somatoform disorders exist at all. So as a concept, it fails on the verifiability requirements of science. In fact, in principle any currently unexplained illness could be classed as somatoform, by the flawed axioms of somatoform disorders. Diabetes, for example, could have be considered somatoform before its physical causes were found.

    In my view, there is not all that much difference between the somatoform disorder concept of disease, and the Medieval concept of malevolent spirits causing disease. Indeed, the efforts of Simon Wessely trying to convince the us that diseases like ME/CFS, irritable bowel syndrome and interstitial cystitis are all somatoform are more akin to pre-scientific Medieval evangelizing than 21st century critical thinking.

    Quoting Harriet: “First you need to do the necessary research to find out if CFS really exists as a definable entity.”

    Well what about depression and schizophrenia? Do we also need to find out if these exist as a definable entities before we do anything to alleviate the misery and suffering of these conditions? There are certainly no accurate objective tests for these conditions, just as there aren’t (yet) for ME/CFS, but that should not stall research into treatment.

    Making ME/CFS into a more precisely definable entity would only take all researchers adopting the same inclusion criteria. The strict and precise “Canadian consensus definition” of ME/CFS has been favored by the more neurologically included researchers. However, the more sloppy “Oxford definition” (so sloppy in fact that it tends to select depressed people, as well as those with ME/CFS) is often favored by psychologists. This sloppiness of definition why a lot of the ME/CFS research performed by psychologists is flawed.

    Quoting Mousethatroared: “As to cognitive dysfunction or “brain fog” – This is also a feature in some diseases and processes, Thyroid disease, Lupus and other systemic autoimmune diseases, menopause, anxiety and depression are the one’s I know off the top of my head.”

    Very true, and that makes brain fog all the more intriguing. It might well be that the biochemistry of brain fog is the same in all these diseases, in which case, studying one disease may help understand brain fog in all.

    In particular, the fact that brain fog in hypothyroidism is cured simply by giving the patient T4 (and sometimes also T3) thyroid hormone replacement means that the conditions under which this brain fog arises are very clearly defined — and this clear-cut case should help uncover the biochemical mechanism of brain fog, if some researcher took interest in it.

  44. Harriet Hall says:

    I don’t think it’s fair to compare CFS to depression and schizophrenia. They have been recognized for centuries and their manifestations have not changed. CFS may be something new… or it may be an old condition dressed up in new clothes.
    It’s really illuminating to read the two books I listed above. There is a long history of classifying unexplained symptoms as everything from a “wandering womb” (hysteria) to “neurasthenia.” At different times in history, patients have manifested paralysis, fits, and other behaviors that were expected and accepted in their society. It wasn’t acceptable to say “I’m too fatigued to function” but it was acceptable to suffer from paralysis or to collapse with bizarre stereotypical fits. As customs changed, the paralyses and fits fell out of fashion and we don’t see them any more. It is abundantly clear that they did not have a definable underlying pathology.

  45. mousethatroared says:

    Hip – “In particular, the fact that brain fog in hypothyroidism is cured simply by giving the patient T4 (and sometimes also T3) thyroid hormone replacement means that the conditions under which this brain fog arises are very clearly defined”

    Yes, it’s often presented to me by doctors as clearly defined, but then you have studies like this –

    http://www.medscape.com/viewarticle/760417_2

  46. mousethatroared says:

    @Hip – sorry, this would have been the better link.

    http://online.liebertpub.com/doi/abs/10.1089/thy.2010.0191

  47. Hip says:

    Quoting Harriet: “There is a long history of classifying unexplained symptoms as everything from a “wandering womb” (hysteria) to “neurasthenia.” At different times in history, patients have manifested paralysis, fits, and other behaviors that were expected and accepted in their society. It wasn’t acceptable to say “I’m too fatigued to function” but it was acceptable to suffer from paralysis or to collapse with bizarre stereotypical fits. As customs changed, the paralyses and fits fell out of fashion and we don’t see them any more. It is abundantly clear that they did not have a definable underlying pathology.”

    The altering array of symptoms manifested in neurasthenia and ME/CFS-like illnesses throughout history is interesting, and these changes do require an explanation. Though the explanation offered by certain psychologists — that manifested ME/CFS symptoms change according to the social customs and fashions of the era — seem absurd and untenable. After all, we do not see the physical symptoms of any other disease vary according to expected and accepted customs.

    I think the very idea that disease symptoms are culturally conditioned reflects the unfortunate tendency of certain schools of psychology to concoct over-embellished explanations for phenomena, with scant regard to the scientific method, which requires that explanatory theories be testable.

    There is a simpler and more plausible explanation for this variation in ME/CFS symptomatology over history, which is as follows.

    As is well-known, there is considerable evidence suggesting that ME/CFS has an infectious etiology, at least in part.

    Certain subsets of ME/CFS actually have a proven infectious cause: Chlamydia pneumoniae, Coxiella burnetii and parvovirus B19 infections are all proven — and largely treatable — forms of ME/CFS. So we know for sure that infectious pathogens can be a cause of ME/CFS symptoms.

    Outside of these proven infectious causes, the majority of cases of ME/CFS are of unproven etiology. However, these unproven etiology cases are often noted to follow an acute infection of some sort, which suggests that the cause may also be infectious. Indeed, one virus that for many decades has been associated with these unproven etiology ME/CFS cases is enterovirus. Recent work by Dr John Chia has show that in 82% of unproven etiology ME/CFS cases, patients have enterovirus protein in their tissue biopsies, compared to just 20% in healthy controls.

    As you are undoubtedly aware, in the Enterovirus genus itself, there are dozens of different enteroviruses, each causing different symptoms, with some non-polio enteroviruses capable of causing transient paralysis. The other interesting and pertinent thing about enteroviruses is that they tend to appear in epidemics: a given enterovirus will remain in circulation for some years, and then disappear again for many years. (Not all viruses behave like this; EBV for example never follows this epidemic behavior.)

    So in my opinion, the most likely explanation for the variations in ME/CFS symptoms over the centuries is simply that in different eras, you get different infectious pathogens appearing in epidemics, and the precise symptoms of ME/CFS will depend on the particular pathogen or pathogens causing ME/CFS in each era.

    In eras when paralysis formed part of the typical ME/CFS symptoms, I suggest this was because at that time, ME/CFS was being triggered by an epidemic of a virus that was capable of causing paralysis. The alternative idea that paralysis was precipitated merely by cultural expectations seems absurd to me. Transient paralysis sometimes occurs in ME/CFS even today (but it is rare), a fact which supports the argument that paralysis is not a symptom determined by the behavioral fashions of an era, but depends on which particular virus you catch, and of course how your body responds to that virus.

    Conditions like depression and schizophrenia have been linked to infectious agents as well, sure, but they are not generally observed to manifest after a trigger infection as ME/CFS often does. By comparison, ME/CFS etiology has a much stronger link to infectious agents, and so you might expect that the nature of this disease will depend much more upon the particular infectious agents in circulation in each era. Depression and schizophrenia are probably more genetically determined, and this is the likely reason that their manifestations do not change much over time.

  48. Sialis says:

    A multidisciplinary team is ideal for many conditions, especially chronic pain; but applying the concept to CFS might be problematic. It would serve to rule out other diagnoses, pick up on other conditions that could be treated, etc. But it might result in unnecessary tests being ordered (each specialist would have his favorite things to pursue) and it might increase the patient’s conviction that something is objectively wrong that is still being missed.

    I’m not familiar with all the nuances of symptoms which would warrant a diagnosis of CFS/ME or FMS, so it is rather difficult and likely inappropriate for me to offer an opinion as to the best type of treatment approach. I do believe that a multidisciplinary team approach, at least for diagnostic purposes, would be best for patients with medically unexplained symptoms, especially those which are significantly impacting their quality of life by either being disabling and/or progressing.

    Doctors aren’t perfect, and the practice of medicine is not always suitable to a cookie cutter approach. It seems that with the more complex, unexplained illnesses a single primary care provider arrangement may not always be best suited to the patient’s needs. Although I wouldn’t necessarily consider them as quacks, there are a lot of primary care and other physicians who seem to hold opinions which are not evidence-based, or are perhaps older approaches that have long since been disproved. Just as patients may be easily duped into believing that acupuncture or NAET, or various untested herbs may offer significant relief, so do too many physicians. Others seem to fear treating any symptoms when they don’t know the specific cause. This leaves those patients suffering and with little treatment options. It is no surprise to me that many turn to alternative providers out of sheer desperation for some relief of symptoms.

    I do feel that patients with unexplained symptoms are too frequently dropped into the CFS/FMS category. Illnesses with objective and observable yet non-specific symptoms are being dismissed into this CFS/FMS category. Furthermore, I think certain SBM physicians, including nybgrus, are perceptive enough to understand how easily patients may indeed be duped (sounds so much better than being made a fool) by certain types of providers, especially those who are relentless in advertising their treatments with misleading information. Patients should be better educated as to the placebo effects as is being discussed here on SBM, but so should physicians. I doubt that most patients understand why they may be feeling a bit better, or think that they feel better, after certain treatments such as acupuncture. It seems too many physicians are either unwilling or unable to explain such effects to their patients. I don’t know why. Uneducated people desperate for relief are most easily fooled. It is unfortunate that there are so many practitioners ready and willing to pounce on such needs and misrepresent the cause, effects and benefits of relatively useless treatments.

    In any case, I am of the impression, and quite possibly an incorrect one, that CFS/FMS are not progressive illnesses, nor do they effect specific body parts consistently and significantly more than others, such as the lymph nodes and salivary glands of the head, neck and under the collar bone, or the intercostal cartilage. On the contrary, CFS and FMS seem like they cause more wide-spread pain of basically equal proportions throughout the body, although the focus of pain may vary from day to day. I could be completely wrong, as I am certainly not a specialist in this area, but those types of conditions are also being diagnosed as CFS/FMS. Patients with symptoms such as these should not automatically be dumped into the CFS/FM category.

  49. irenef says:

    @Harrit Hall:

    “The history of medicine is full of diseases with changing names that all involve “a fascinating array of strange symptoms,” and many of those symptom complexes have come and gone according to societal perceptions (“fads”). It would probably make more sense to study that spectrum, in the light of history, rather than just what is currently designated CFS. My personal guess is that we will eventually learn that a few patients with an objective disease are being lumped together with a lot of people who have somatoform disorders and psychological problems. Until that can be sorted out, research just adds to the confusion.”

    Historical fads are interesting, but it’s difficult to diagnose people after they are dead and gone. Vocabulary changes, too; “soldier’s heart” is nowadays called PTSD. (I always wondered what Dostoyevsky meant by “brain fever”.) Perhaps all those Victorian neurasthenics really did suffer from CFS; maybe some of them had pernicious anemia, MS, or chronic low-level infections.

    The somatoform disorders have case definitions that differ from case definitions of CFS. So do psychological problems.

    “. . . research just adds to the confusion.”

    What you are implying is that CFS is not a “real” disease because there is no diagnostic test for it. Do I really need to remind people that absence of evidence is not evidence of absence? It seems as if your underlying objection to medical treatment of CFS patients is that we are not really sick.

    And how could research add to the confusion?

  50. Harriet Hall says:

    Women in the 19th century had bizarre fits and paralyses and strange behaviors that bore no resemblance to anything reported by CFS patients, and that have gone out of fashion and no longer occur. Other well-described patients in history manifested the same nonspecific symptoms as CFS patients, and there have been many different names and explanations for those symptom complexes. Trying to study “neurasthenia” or “hysteria” were not productive avenues of research. I am not implying that CFS is not a real disease or that patients are not really sick, I’m just pointing out that once-popular diagnoses have vanished, and others have been re-categorized, so we need to be very careful to define what is being studied. I think most of us would agree that at least some CFS patients are misdiagnosed. Research adds to the confusion when multiple poorly defined conditions are lumped together and research looks at the lump rather than the components.

    Incidentally, Da Costa’s “soldier’s heart” was very different from PTSD. See http://en.wikipedia.org/wiki/Da_Costa%27s_syndrome and http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001923/
    There is some overlap of symptoms, but not enough to confuse the two diagnoses.

  51. WilliamLawrenceUtridge says:

    What you are implying is that CFS is not a “real” disease because there is no diagnostic test for it. Do I really need to remind people that absence of evidence is not evidence of absence? It seems as if your underlying objection to medical treatment of CFS patients is that we are not really sick.

    There is a germ of an idea in your objection, that people who have psychologically-based diseases are not really sick, that CFS must have a biological cause, and that if it doesn’t it’s somehow less worthy for respect and treatment. I agree that society in general is not very good at treating, dealing with or understanding mental illness or psychological suffering. I agree it is hard for psychogenic conditions to get respect, despite how profoundly miserable they can make sufferers. I can see why CFS patients object to any psychological attributions for their condition.

    That does not mean that CFS has a biological cause for all patients. There is a very good case to be made that CFS has, for some patients, a purely psychological cause. Again, with a wastebasket diagnosis, it’s nigh-impossible to tell.

  52. nybgrus says:

    I’ve only just now read through in detail the last few comments. The first thing I’d like to clear up:

    I think certain SBM physicians, including nybgrus, are perceptive enough to understand how easily patients may indeed be duped

    Firstly, thank you for the kind words. But more importantly, I am not a physician. I am currently in my 4th (last) year of medical school and will graduate as a physician this year. I will still have my residency training and then fellowship after. I apologize if I unintentionally gave the false impression that I am already a physician, let alone a trained one. I use terms such as “my patients” or “our patients” since I do, in fact, see patients and help manage their care in the course of my rotations. I also feel like they really are “our patients” since I am indeed soon to be a physician and I fully believe in the teamwork model of patient care.

    What you are implying is that CFS is not a “real” disease because there is no diagnostic test for it. Do I really need to remind people that absence of evidence is not evidence of absence? It seems as if your underlying objection to medical treatment of CFS patients is that we are not really sick.

    I also agree with Dr. Hall and WLU – psychiatric/psychological illness has an unfair and unreasonable stigma surrounding it. Those with psych disorder/disease are truly suffering just as much as someone with organic disease. I believe that at least a big part of this stigma comes from the religious notion of a mind-brain duality with a soul being the seat of free will and cognition. Thus if it is “in your head” it is somehow not only divorced from your physical self but also changeable at your whim, thanks to the fact that you have free will. Both notions (duality and free will) make no sense in the modern neuroscientific era. But the stigma persists.

    Lumping together a number of different conditions with different underlying etiologies but similar manifestations is indeed counterproductive. I have argued here that depression is an excellent example of this. If one looks at the various treatments for depression, how well they work (and don’t work), how much crossover there is, and the evidence for improvement from doing nothing in certain cases, the only reasonable conclusion is that the entity we call “depression” has a number of differing etiologies. The fact that this is the case, but it is all researched as one entity based on the neurotransmitter hypothesis has lead to a slew of attacks against psychiatry in general and anti-depressant medications in specific since, as we know, each drug only seems to help about 60% of people. This is also likened to the efficacy from talk therapy which becomes called a placebo and thus justifies attacks on neuropharmacotherapy. I have argued before that talk therapy is not placebo, but I won’t get into exactly why now. The reality is that the most reasonable explanation is at least 2-4 underlying etiologies all manifesting as “depression” getting lumped together. We simply don’t have the technological sophistication nor the detailed understanding to have a higher resolution of the underlying etiologies to target treatment better. So we must do trial and error. Which leads to disparaging comments and often patient despair since after the 2nd or 3rd failed attempt they feel we don’t know what we are doing (which is actually partially true).

    That doesn’t mean we shouldn’t study depression or CFS/ME. It just means that we should learn our lesson and first focus on a more rigorous definition and diagnostic criteria before attempting to do clinical trials to treat, since otherwise we are inevitably lumping together disparate underlying etiologies and that will dilute our ability to actually determine what treatments work for specific subsets of CFS/ME. We may find a fantastically useful treatment for a particular subset, but because we have lumped in a different one with a different etiology, the results could look borderline or even negative. We then discard the attempted treatment (or it becomes maligned by some and overused by others like anti-depressants) at great disservice to that subset of CFS/ME patients.

    It also leads to so many different causes fighting to be the cause of CFS/ME. Like the virus induced hypotheses. I have no doubt that is actually a subset. How big a subset? How to treat? Prognosis? Completely obfuscated by the catch-all nature of the diagnosis. The same goes for psychogenic etiologies, etc.

    I believe this is what Dr. Hall has been saying. It sucks, to be sure. But such is the nature of science and the slow, but steady, progress it entails.

  53. Harriet Hall says:

    Nonspecific symptoms are ubiquitous. It’s called “being human.” See http://skepticalmothering.com/2013/01/16/do-you-have-forers-disease/ That’s why it’s so difficult to study diagnoses that depend largely on such symptoms.

  54. Sialis says:

    Nonspecific symptoms are ubiquitous. It’s called “being human.” … That’s why it’s so difficult to study diagnoses that depend largely on such symptoms.

    “Non-specific” was a poor choice of words on my part. What is the proper term to describe a specific recurring symptom which is not indicative of a particular or specific disease process – Such as these transverse nail ridges, and given that they are not caused by nail bed trauma or diabetes. http://en.wikipedia.org/wiki/Beau%27s_lines

    http://dermatlas.med.jhmi.edu/image/Beau_Line_1_040130

  55. jasonBayArea says:

    @nybgrus- You comment that 60% of people appear to be helped with anti-depressants and

    “That doesn’t mean we shouldn’t study depression or CFS/ME. It just means that we should learn our lesson and first focus on a more rigorous definition and diagnostic criteria before attempting to do clinical trials to treat, since otherwise we are inevitably lumping together disparate underlying etiologies and that will dilute our ability to actually determine what treatments work for specific subsets of CFS/ME. ”

    Is there evidence out there that any of the currently approved anti-depressants work on 60% of patients? The studies I have read indicate that the percentages are much lower; therefore using the current crop of anti-depressants on patients is potentially unethical since the side effects will usually outweigh the null positive effects. And despite the lack of rigorous definitions for depression, recent studies on ketamine have been showing incredible promise. As far as I have read, this is primarily based on patient self-reports. Because major depression is considered such a dangerous disease, researchers have been prepared to try different treatments and then figure out the mode of action. Early evidence indicates that NMDA receptors are much closer to the root of some (likely most) cases of depression than serotonin receptors.

    Should researchers not try different drugs on depression because we aren’t good at breaking down subsets and root causes?

  56. Scott says:

    IANAD, but that’s my understanding of “non-specific” exactly – the symptom is not specific to any particular disease. It doesn’t mean “inexactly specified” in this context.

    So “fatigue” is an exact symptom. But it is characteristic of many different conditions, so it is still “non-specific.”

    I’m sure Dr. Hall will correct me if I am wrong.

  57. Sialis says:

    Nonspecific symptoms are ubiquitous. It’s called “being human.” … That’s why it’s so difficult to study diagnoses that depend largely on such symptoms.

    “Ubiquitous” is defined as found everywhere or constantly encountered. I would consider fatigue, low back pain, headache, muscle soreness, etc., as ubiquitous. This particular non-specific symptom of transverse nail lines is not so common as to be found everywhere. It is not a common finding in general, and certainly most physicians do not easily or readily recognize it in my experience.

    One would of course have to consider such symptoms in conjunction with the patient’s other symptoms. Transverse ridges, granuloma annulare, muscle tremors and spasms and fasciculations, ‘burning’ sensation of all salivary glands and lymph nodes throughout the head, neck and under the collar bone, plus severe intercostal and ‘neck’ pain, and biopsy diagnosed significant small-fiber neuropathy. In combination, are these symptoms considered ubiquitous, non-specific and “being human”? Moreso, and if so, would and should they be considered as deserving no treatment, not even palliative care? And what care, if any?

  58. Harriet Hall says:

    @Scott,

    ““fatigue” is an exact symptom”

    Not really. I would call it both non-specific and inexactly specified. It depends on self-reporting, varies with patient perception of whether it is severe enough to report, and is really pretty nebulous.

    Compare to nausea and vomiting. Vomiting is an exact symptom: emesis can be witnessed and measured. Nausea? We have to rely on the patient’s report of how he feels. What may be minor queasiness to one person, easy to disregard and not worth complaining about, might be reported as significant nausea by another person. And the self-reporting of one patient may change from moment to moment depending on distraction, emotional state, and other factors.

  59. Hip says:

    It is interesting that in the Wikipedia articleof the above mentioned Da Costa’s syndrome, it says that Da Costa noted that this condition often developed and persisted after an initial bout of fever or diarrhea.

    Now, the occurrence of fever or diarrhea tends to indicate that an individual has contracted an infection. Since in recent years, diseases of unknown etiology are being increasingly linked to infectious agents, one might read Da Costa’s observations as a clue that Da Costa’s syndrome was in fact precipitated by a chronic infection, rather than a somatoform disorder.

    To me, designating a disease as a somatoform disorder is the ultimate wastebasket and waste of time etiological description.

  60. mousethatroared says:

    Scott,
    ““fatigue” is an exact symptom”
    Harriet Hall – Not really. I would call it both non-specific and inexactly specified. It depends on self-reporting, varies with patient perception of whether it is severe enough to report, and is really pretty nebulous.”

    Yeah – I can think of several kinds of sensations of “fatigue” or tiredness
    There’s – I’m falling asleep in the middle of dinner tiredness
    There’s – I have the flu and just moving feels like too much effort tiredness.
    There’s – I just don’t have any pep for the last couple months.
    There’s when I lift or carry things that normally don’t take any effort I get tired and have to rest.
    There’s the high gravity day where everything seems like more effort, but which feels distinctly different than the other effort related tiredness.
    Then there’s that sort of fatigue where you feel like you are just emotionally battling the events of the day and have had enough.

    Just when I think that I can really connect one particular kind of fatigue to a cause, say – lack of pep to hypothyroid – things stop lining up. Maybe the TSH testing thyroid levels was normal, but the chest sounds wheezy. It’s a pain in the rear.

    Unfortunately the body doesn’t seem polite enough to send unique signals for every ailment.

  61. nybgrus says:

    Unfortunately the body doesn’t seem polite enough to send unique signals for every ailment.

    One might be tempted to call that a design flaw.

  62. Sialis says:

    To me, designating a disease as a somatoform disorder is the ultimate wastebasket and waste of time etiological description.

    Along the lines of Dr. Novella’s post about why people turn to alternative treatments, I think when people have exact symptoms, but which are not indicative of any particular disease process, and those people are left without any treatment or pallative care while the symptoms progress, they will continue to search for answers. If they are readily dismissed as having a somatoform disorder, or told that the source of their symptoms is unknown, then they will continue to research and search for a cure or at least pallative care.

    Uneducated patients (any many medical providers) who don’t recognize the deceptive advertising for certain alternative treatments, like those promoting acupuncture to treat disease, could most easily be lured into a bogus series of treatments. I find this especially true when one is given misinformation about other well-known conditions by medical experts. If the patient knows an expert is incorrect in their statements about something, they may rationalize that the same expert might be misinformed or uninformed about other things. So the patient keeps searching…

  63. mousethatroared says:

    nybgrus
    “One might be tempted to call that a design flaw.”

    I keep sending letters to the management, but they haven’t responded yet. Poor customer service, I say.

  64. Hip says:

    There is a very interesting article just published on Cort Johnson’s new ME/CFS website, on the subject that fatigue may not be the most important symptom in ME/CFS, and that other symptoms such as sensory gating dysfunction may better characterize ME/CFS.

    See here:

    NOT FATIGUE AFTER ALL? NEW MODEL SUGGESTS OTHER SYMPTOMS BETTER EXPLAIN CHRONIC FATIGUE SYNDROME

  65. nybgrus says:

    I keep sending letters to the management, but they haven’t responded yet. Poor customer service, I say.

    I’ve often wondered if there is even anyone in the office.

  66. mousethatroared says:

    nybrgus Ha! I was originally trying to make a joke about how my brain or nervous system isn’t running things as well as I’d like…rather than any intelligent design reference.

    So, if I’m talking about my brain/nervous system, I’m pretty sure the “management” is in the office, they just generally ignore my calls. If we’re making religious references…I haven’t the slightest.

    You gotta watch me, I tend to anthropomorphizes everything. Evolution, my nervous system, god(s), the freeway system…all occassionally conceived as sentient entities whose sole purpose is to inconvenience me.

  67. PernilleN says:

    @Nybgrus: ” Those with psych disorder/disease are truly suffering just as much as someone with organic disease.”

    Are you saying the brain is not an organ? ;)

    @WilliamLawrenceUtridgeon
    “That does not mean that CFS has a biological cause for all patients. There is a very good case to be made that CFS has, for some patients, a purely psychological cause.”

    Are you saying psychology is not biology?

    I’m sure neither of you mean to say that mind and body are completely different entities, but I do wish we could start using different words when we talk about psychological disease. It is just as much biological as hepatitis or the flu. The brain, the mind, emotions, thoughts, are biology, the brain is actually the most important organ. There’s no such thing as a purely somatic disease. There’s no such thing as a purely psychiatric disease. Human beings don’t consist of a brain linked to a body, we are one organism with many many intertwined systems. More and more research the past years has shown how closely linked “mind” and “body” are, to the point where distinguishing between them is impossible, and without meaning.

    But as Nybgrus says, the stigma persists, and many patients are furious at the notion that they may also have psychological issues. They think that means we think they are crazy, or stupid, or hypochondriacs, and “not really sick”. I understand why they react that way, but it’s saddening. We (both doctors and the public) should know better by now.

    And perhaps the most saddening thing: When people so vehemently protest at the notion that they might have “something” psychological, what does that say about our attitudes towards people with “real” psychiatric disease?

    Regards,
    Pernille Nylehn

  68. daedalus2u says:

    The best, and I think determinative diagnostic test for CFS is post exertional malaise. You do an exercise to exhaustion on an ergometer where you can measure the work output and also O2 consumption and CO2 production, so you know when there is O2 debt and the real lactate threshold.

    This easily distinguishes between people who are weak from detraining and from those who are weak from CFS. But people with CFS will be incapacitated for days, so it is not a test to be done lightly.

  69. PernilleN says:

    @daedalus2u: What if the patient has COPD? They wont be invalid for days after the test, of course, but they will probably have O2 debt and lowered lactate thershold.

  70. nybgrus says:

    @PernilleN:

    You are absolutely correct. And I do believe your comment to me was indeed tongue in cheek. However, if you look through my history of posts here you will find that I (often fiercely) advocate for the realization that psychiatric disease is exactly that – organic disease. Unfortunately the language persists and is actually particularly entrenched in medicine. I agree that it should change and I think it will… eventually. But in all honesty probably not in my career and maybe not even in my lifetime.

    Another aspect that I frequently comment on – both here and in my professional and personal life – is the notion of “talk therapy.” It is often used as a “placebo” and thus studies comparing “talk therapy” to pharmaceuticals can show equivalency and give fuel to the notion that neuropharmaceuticals (NPs for shorthand purposes here) are ineffective compared to placebo. Even in cases where active NPs are compared to a sugar pill, there is still actually no real “placebo.” When the organ of concern is the brain, we must realize that doing anything whether it be talking to the patient or giving them a sugar pill or even just giving them a hug is an active intervention that changes the neural cytoarchitecture of the person in question. We have good data demonstrating neural plasticity is extremely robust and that changes can and do happen on timescales as short as minutes with things like Hebbian learning cementing in those changes. This is, IMHO, the most parsimonious explanation as to why mild to moderate depression (for example) seems to have a fair bit of equivalence between NPs and “talk therapy” and even placebo, but severe depression is much more refractory and NPs show a greater response (and why CAMs such as St. John’s Wort seem to have effect for mild depression). The same with schizophrenia and pretty much any psychiatric disease. Just doing something has an actual and direct effect on the affected organ. The same cannot be said for kidney disease, for example. This muddies the waters and the old notions of “it’s all in your head” make people blind to these facts and their ramifications (that and religion, but I won’t go there).

    The varying underlying etiologies of phsyciatric disease which we do not have the resolution to discern at this time plus the direct effects of literally any sensory input in changing the neural cytoarchitecture and neurotransmitter release and receptors with the fact that we are our neural cytoarchitecture explain (once again, IMHO – I am not an expert in these things at all) many of the “anomalies” we find in the data and should absolutely obviate the stigma associated with psychiatric disease.

    We’ll get there on day. Such is the awesome power of the slow lumbering beast we call science.

    As for D2u’s lactate/oxygen idea…. well, last night was the induction ceremony and celebration for the newly minted Year 3 students as they start their clinical work so my brain is very slow this morning and I simply can’t comment. Nor can I write as cogently as I normally do, as clearly evinced above.

  71. daedalus2u says:

    Here is an article on CFS and post-exertional malaise.

    http://www.cfids.org/cfidslink/2010/080402.asp

    I don’t know about COPD. I think that someone can have both COPD and CFS simultaneously, but which would dominate is likely to be idiosyncratic.

    Post-exertional malaise occurs in the muscles. COPD starts out as more of a lung thing, but eventually everything else gets involved too. Once the muscles get involved, then it is CFS too. If supplemental oxygen doesn’t improve exercise performance, then the lungs are not the limiting factor. This is the case in CFS and it does become the case in COPD.

    The point of doing the O2/lactate threshold is to ensure that equivalent states of O2 debt are reached in the muscle. The post-exertional malaise is (I think) due to destruction of mitochondria and their very slow replacement.

  72. PernilleN says:

    @daedalus2u: I agree with most of ypour reasoning, but I’m not so sure about this one:

    “COPD starts out as more of a lung thing, but eventually everything else gets involved too. Once the muscles get involved, then it is CFS too.”

    I don’t think it’s wise to muddy the waters even more by defining serious COPD as a form of CFS. Especially since CFS is more than fatigue and post-exertional malaise. People with grave COPD tire easily, of course, since they hardly ever get enough oxygen, but they don’t have all the other symptoms og CFS. And, even more important, they respond well to exercise and physiotherapy, which ME/CFS-patients usually don’t, unless the exercise is very very light.

    @Nybgrus: I do know your stance on mind-body, so it was probably unfair to pick on you, since your remark was obviously a slip of the tongue. But I picked on you anyway, to demonstrate how even the most conscientous tend to be trapped by language and traditional thinking.

    As for “anything we do to a person changes their does something to their mind”, making psychiatric treatment difficult to evaluate: I think you are exaggerating a bit. Of course everything we do to a person – a chat, a hug etc – does something to his neural pathways. But it is still perfectly possible to distinguish between placebo effect and treatment effect. After all, hugging and chatting are hardly systematic interventions, while therapy is – be it psychotherapy, CBT or whatever.

    Regards,

    Pernille Nylehn

  73. daedalus2u says:

    I think that when COPD progresses to cachexia, then it is like the other disorders that have progressed to cachexia, chronic heart failure, chronic kidney failure, chronic liver failure, and Alzheimer’s.

    Those tissue compartments are all high metabolic organs. If mitochondria biogenesis becomes compromised, then patients become hypermetabolic as the existing mitochondria get pushed to higher potentials where there is more “slip” (less ATP per molecule of O2). Metabolism isn’t doing more, it is doing less, but doing it with ATP that is generated less efficiently.

    Mitochondria wear out over time (few months), and if they are not replaced, eventually they fail and the tissue compartment with too many failed mitochondria fails too. That can happen quickly during sepsis where it causes multiple organ failure. What does it look like if the failure is more gradual? I think it looks like the chronic degenerative diseases of each particular organ. The high metabolic rate organs are more susceptible to this type of failure, so we have specific names for them.

    As all of them get worse, eventually they start looking more and more similar and with vascular effects. When you start getting ectopic fat is when things are really bad. Visceral fat is not that bad, liver fat is worse (but still pretty common), but ectopic fat in the heart or kidney is a lot worse.

    I see post-exertional malaise in CFS as the acute failure of too many mitochondria in muscle.

  74. PernilleN says:

    I have no problem with your reasoning about mitochondria etc. But you still can’t say CFS is the same, or somilar, to grave heart- or lung disease. Even you mean only the post-exertional malaise – COPD patients aren’t incapacitated for days after exercise, even when they are cachectic. They get better and better with exercise, even if it’s strenuous. I’ve tried rehabilitating both heart/lung patients and CFS patients, and there’s a vast difference.

    Regards
    Pernille Nylehn

  75. nybgrus says:

    I do know your stance on mind-body, so it was probably unfair to pick on you, since your remark was obviously a slip of the tongue. But I picked on you anyway, to demonstrate how even the most conscientous tend to be trapped by language and traditional thinking.

    Indeed. Not so much a slip of the tongue, but a necessity of communication within the current nomenclature of medicine. Trapped indeed – there is no particularly good way to express the notions without long explanations; explanations which most people don’t care to hear about and many would not accept at face value since it is counter to their “intuition” on the topic. As I said, I think this is changing, albeit slowly, and will eventually be the way psychiatry moves forward. At base, good psychiatry is a scientific discipline and they are making good strides in a positive direction. Anyways, I’ll quit now lest I start pontificating too much and extrapolating beyond reason. I’m certain you and others here get the gist of what I am trying to say.

    As for “anything we do to a person changes their does something to their mind”, making psychiatric treatment difficult to evaluate: I think you are exaggerating a bit.

    Perhaps I am. But don’t you think it is a reasonable thought that those who have depression would be benefitted merely by having more attention paid to them and “something to do” every day as part of simply being in a trial? Just having others to converse with, care about their problems, and take pains to ensure ethical standards are met is certainly helpful and in some cases of mild depression with a specific etiology amenable to it can be curative. This, I think, is uncontroversial. My only contention is that these factors are not placebo effects – they are active interventions since they all actually actively and directly influence the pathological organ – the brain.

    So when people – critics especially – look at studies and see not much difference between an active pharmaceutical treatment arm and the placebo pill arm of a trial, they are actually comparing 2 active treatments to 1 active treatment. Furthermore, my contention is that depression as an entity is difficult to define precisely, is obviously a continuum, and (my biggest leap, though obviously I think it is justified) that the same disease state has multiple etiologies that we simply cannot distinguish. In at least some of these etiologies and especially along the lower end of the severity continuum we would expect to find that 1 active treatment (the “placebo”) is clinically significant and the 2nd (drugs) doesn’t actually add much to the treatment (in other words, it is overkill). Thus, the clinical outcomes between the two groups doesn’t appear as large and those who merely look at that on face value conclude that drugs don’t have benefit (or at least not much) to patients since “placebo” works very well and has a large clinical effect size.

    Since we randomize after the diagnosis is made, I am arguing that any given series can have an unkown number of depressive patients in either arm of the trial who will respond favorably to the “placebo” treatment (which I am further arguing is actually an active treatment) and thus explains the heterogeneity of studies and the varying response rates in different arms of different trials that we see.

    And yes, structured CBT would likely be more effective but perhaps not much more than the aggregate of “placebo” effects in studies. What it certainly would be is more consistently effective. But we have good data to demonstrate that the precise method of “talk therapy” is significantly less important than how well the patient gets on with the practitioner. This, to me, fits in with the fact the neurobiology is complicated and thus different “styles” will fit different people better and be more able to effect change in the neurophysiology of the patient in question.

    So systematic interventions are necessary to invent and study so that we can have a baseline of standardization and understanding but we see that because we are complex and variation in neurobiology is much more than in the rest of our biology, small non-sytematic things like hugging and chatting can be extremely profound in some, neutral in others, and in some even be detrimental. But all active treatments which can and do easily confound studies.

  76. daedalus2u says:

    There are issues with calling treatments “active” or “placebo”, without knowing the mechanism(s) by which they have effects.

    The definition of “placebo” that I like, is an effective treatment that has positive therapeutic effects mediated not through pharmacology, surgery, or other direct, physical effects.

    A treatment that has no therapeutic effects is an ineffective treatment, no matter what its treatment modality. A treatment that does have positive therapeutic effects is an effective treatment, no matter what its treatment modality.

    Placebos can have positive treatment effects. Distinguishing the placebo-mediated therapeutic effects from the pharmacologically-mediated therapeutic effects is important for clinical trials to compare treatments, it is not so important in treating patients in the absence of a clinical trial.

    If the definition of a non-placebo hinges on it being systematic and ritualized (as in psychotherapy), then acupuncture is no less systematic and ritualized. An ineffective pharmacological treatment can have positive treatment effects through the placebo effect.

  77. hixxy82 says:

    I’m somewhat offended by the links to ClinicalTrials.gov provided by The Dave that weren’t even searched correctly. Try using “quotes” around phrases next time. There’s even an example at the website right next to the search box.

    Here are some more informing statistics from ClinicalTrials.gov

    Myalgic Encephalomyelitis

    23 studies found for: “myalgic encephalomyelitis” | Open Studies
    23 studies found for: “chronic fatigue syndrome” | Open Studies

    The above studies overlap

    Prevalence:

    0.2% – 0.7% (0.45% avg) https://www.mja.com.au/journal/2002/176/9/chronic-fatigue-syndrome

    0.015% – 0.2% (0.1075% avg) http://www.biomedcentral.com/1741-7015/9/91

    0.007% (7:100,000) – 3% (3000:100,000) (1.5035% avg) http://en.wikipedia.org/wiki/Chronic_fatigue_syndrome

    Overall average 0.687%

    Studies per sufferer: 23 / 0.687 = 33.47889374090247

    If I had just taken the prevalence statistics from wikipedia like the other disease, the result would be even worse.

    ——————————–

    Crohns

    217 studies found for: crohns | Open Studies

    0.029% (29:100,000) – 0.199% (199:100,000) (avg 0.2445%) http://en.wikipedia.org/wiki/Crohn's_disease

    Studies per sufferer: 217 / 0.2445 = 887.5255623721881

    ——————————–

    Multiple sclerosis

    0.00002% (2:100,000) – 0.15% (avg 0.07501%) http://en.wikipedia.org/wiki/Multiple_sclerosis

    299 studies found for: “Multiple sclerosis” | Open Studies

    Studies per sufferer: 299 / 0.07501 = 3986.135181975737

    ——————————–

    Systemic lupus erythematosus

    0.04% (40:100,000) – 0.159% (159:100,000) (avg 0.0995%) http://en.wikipedia.org/wiki/Systemic_lupus_erythematosus#Epidemiology

    125 studies found for: ” Systemic lupus erythematosus” | Open Studies

    Studies per sufferer: 125 / 0.0995 = 1256.281407035176

    ——————————–

    Schizophrenia

    0.3% – 0.7% (avg 0.5%) http://en.wikipedia.org/wiki/Schizophrenia#Epidemiology

    605 studies found for: Schizophrenia | Open Studies

    Studies per sufferer: 605 / 0.5 = 1210

    ——————————–

    I would be much easier to live with a disease knowing that all that can be done is being done, but that plainly isn’t so. I’m sure you could continue going through many more diseases and you would find the this disease comes out far worse off the whole way through.

  78. Sialis says:

    What I wonder sometimes is whether patients diagnosed with CFS/ME or FMS really suffer from genetic conditions or other illnesses instead. Mitochondrial diseases are ones that I often consider. In my experience, patients are not routinely tested for any genetic or environmentally triggered hard to diagnose or rare diseases unless perhaps their symptoms are profoundly visible or imminently life-threatening. It is relatively easy after a few years of complaining to physicians to find one willing to test for more common illnesses, like Sjogren’s, Lupus, and Scleroderma, but any further testing is generally refused. If it doesn’t show up in the basic blood work, the patient is refused care, and many are indeed generally given a psychiatric diagnosis of some kind, especially women. I know this is an area of much disagreement between physicians and patients, and I only speak from the patient perspective.

Comments are closed.