EDS, hypermobility, and the link, if any, to ME/CFS

Discussion in 'Fibromyalgia and Connective Tissue Disorders' started by Milo, May 22, 2019.

  1. Milo

    Milo Senior Member (Voting Rights)

    Moderator note:
    This post has been copied and posts responding to it have been moved from this thread:
    Jen Brea: My ME is in remission

    Hypermobility is also discussed on this thread:
    Concerns about craniocervical instability surgery in ME/CFS

    Jen, we need to be careful here. hEDS does not equal ME. hEDS is a much contested diagnosis here, and it is important not to lump everything under one umbrella. It reminds me of Central Sensitization theory.
    Last edited by a moderator: May 26, 2019
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  2. WillowJ

    WillowJ Senior Member (Voting Rights)

    hEDS is real. Some people have gotten confused because of the existence of BJH asymptomatic JH (joint hypermobility without any bothersome symptoms) and don't realize that hEDS is not only about joints, but this is their own problem and not the hEDS patients'.

    However I agree that it's not good to just lump a bunch of things together into one category or conflate treatment for one disease with treatment for a different disease.

    What is good is for different neglected disease groups to be working together to solve barriers we have in common.

    Edit: I got terms mixed up. GJH (general joint hypermobility, or just JH) is hypermobility that doesn't have to have symptoms. BJH (benign joint hypermobility) is a syndrome with signs and symptoms.

    The more expert usage:

    PPS, Milo I didn't intend to pick on you. There's some incorrect information going around is all. Believe patients. Thanks.

    ppps, Also edited for tone.
    Last edited: May 26, 2019
  3. WillowJ

    WillowJ Senior Member (Voting Rights)

    That's just for hypermobility, which may or may not be a disease, depending on whether or not it's bothersome.

    hEDS is not diagnosed by Beighton. Beighton was never intended for clinical diagnosis, and should never be used for that. hEDS is diagnosed by Brighton (Tinkle update), now by 2017 Tinkle or whomever. This involves looking at hypermobility, family history, and other signs and symptoms. It is indeed a clinical diagnosis, but many diseases started with clinical diagnoses.

    ME has a clinical diagnosis currently.

    That doesn't make a diagnosis invalid.
  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    Pardon me for saying but I do know about Beighton, which was used for clinical diagnosis routinely in the clinic I did with Rodney Grahame in the 1970s. I also know about Brighton, which is just as arbitrary. I published one of the first clinical research papers on this stuff with Grahame in the late 70s. Embarassingly the paper came to an invalid conclusion and effectively showed that its authors were trying to prove a contradiction. It taught me a lot about how not to do research.
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  5. WillowJ

    WillowJ Senior Member (Voting Rights)

    There's no proper citation, but this blog claims Grahame and Brighton Beighton say it was designed for epidemiological research, and while it was used clinically, that wasn't the original purpose.

    Last edited: May 26, 2019
  6. WillowJ

    WillowJ Senior Member (Voting Rights)

    PS, that is not a useful critique. In the first place there are no details.

    In the second place, there are papers at least as recent as 2017 (perhaps newer).
    Last edited by a moderator: May 24, 2019
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  7. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK

    So why did Rodney get me to do a Beighton score on every patient when I arrived fresh as a junior registrar? I don't mean to be rude but I was actually significantly involved in the whole business of upgrading 'BHS' into 'hEDS' in the very early days. I was there in the clinic with Rodney using Beighton every week. Beighton is right that the main value of his score was as a research tool - simply because measuring hyper mobility in the clinic is probably a fairly useless exercise. But if a diagnosis was to be made of BHS then it was always made on the basis of a Beighton screen - not surprisingly since there isn't really any other way to do it.
  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    I was saying that my own paper was crap. This is the paper https://www.ncbi.nlm.nih.gov/pubmed/7332373

    The idea of the paper was to show that people with benign joint hypermobility, defined as hyper mobility in the absence of features in internal organs, had an increased prevalence of mitral valve prolapse. They didn't but something funny happened with the data so it looks as if they did.

    But note that if they did they couldn't by definition have benign hyper mobility syndrome - hence the attempt to prove a contradiction.

    As far as I can see much the same people have been going round in similar circles for the last forty years. Rodney has finally retired and Alan Hakim, who was one of our trainees, has taken over. At least until five years ago I assiduously attended presentations to see if anything new of significance had been discovered. Apart from finding some genes all I was aware of wa the continued reiteration of un documented clinical narratives.
    Last edited by a moderator: May 26, 2019
  9. WillowJ

    WillowJ Senior Member (Voting Rights)

    I can't say for sure as I am not Rodney Grahame, but I would imagine this would be because Beighton score is one of the components of Brighton criteria (or else that was prior to 1998 or whenever Brighton first came into use?). Although some rheumatologists do indeed use Beighton for diagosis of hEDS, this is unfortunate because that's not the best practice criteria.

    By itself, Beighton is not diagnostic of anything besides hypermobility (which may or may not be related to a disease).

    Brighton criteria (2000, revised from 1998, Grahame R, Bird HA, Child A. ):

    Diagnosis is made by 2 major critiera,
    or 1 major and 2 minor criteria,
    or 4 minor criteria.

    Exclusions are Marfan syndrome, or Ehlers-Danlos syndromes of types other than III/hypermobility type.

    Major criteria:
    1. A Beighton score of 4/9 or greater (either currently or historically).
    2. Arthralgia for longer than 3 months in 4 or more joints.
    Minor criteria:
    1. A Beighton score of 1, 2, or 3/9 (0, 1, 2, or 3 if aged 50+) [cannot be combined with Major criteria 1].
    2. Arthralgia (3 or more months) in 1-3 joints, or back pain (3 or more months), spondylosis, spondylolysis/spondylolisthesis. [cannot be combined with Major criteria 2].
    3. Dislocation/sublixation in more than one joint, or in one joint on more than one occasion.
    4. Soft tissue rheumatism with 3 or more lesions (e.g. epicondylitis, tenosynovitis, bursitis).
    5. Marfanoid habitus (tall, slim, span/height ratio > 1.03, upper:lower segment ration <0.89, arachnodactyly [+ Steinberg/wrist signs].
    6. Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring.
    7. Eye signs: drooping eyelids or myopia or [redacted].
    8. Varicose veins or hernia or uterine/recal prolapse.

    2017 (regarding all types of EDS):
    https://www.ncbi.nlm.nih.gov/pubmed/28306229 (Malfait, Francomano, Tinkle, et al. [including Grahame as well as 41 other authors])

    Both criterion 1 and criterion 2 must be met to make a diagnosis

    Criterion 1: Generalized joint hypermobility:
    Beighton scrore 6 or more for pre-pubertal children and adolescents, 5 or more for men and women up to 50 years old, and 4 or more for those 50 or older.

    In those with acquired joint limitations, use the 5-point questionnaire below. If the Beighton score is missing only 1 point for the category and two points are gained with the questionnaire below, then this criterion is met.

    1. Can you now (or could you ever) place your hands flat on the floor without bending your knees
    2. Can you now (or could you ever) bend your thumb to touch your forearm?
    3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? [without training for the splits]
    4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
    5. Do you consider yourself “double-jointed”

    Criterion 2: Two or more among the following features A, B, and C must be present (for example, A and B; A and C; B and C; A and B and C)

    Feature A: systemic manifestations of a more generalized connective tissue disorder (a total of five must be present)
    1. Unusually soft or velvety skin
    2. Mild skin heperextensibility
    3. Unexplained striae such as striae distensae or rubrae at the back, groins, thighs, breasts and/or abdomen in adolescents, men or prepubertal women without a history of significant gain or loss of body fat or weight
    4. Bilateral piezogenic papules of the heel
    5. Recurrent or multiple abdominal hernia(s) (e.g.,umbilical, inguinal, crural)
    6. Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS
    7. Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without a history of morbid obesity or other known predisposing medical condition
    8. Dental crowding and high or narrow palate
    9. Arachnodactyly, as defined in one or more of the following: a.positive wrist sign (Steinberg sign) on both sides; b.positive thumbsign (Walker sign) on both sides
    10. Arm span-to-height ≥1.05
    11. Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
    12. Aortic root dilatation with Z-score >+2

    Feature B: positive family history, with one or more first degree relatives (biological mother, father, brother, sister) independently meeting the current diagnostic criteria for hEDS.

    Feature C: musculoskeletal complications (must have at least one)
    1. Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months
    2. Chronic, widespread pain for ≥3 months
    3. Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b)a. Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times b. Medical confirmation of joint instability at 2 or more sites not related to trauma

    Criterion 3: all the following prerequisites must be met:
    1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS
    2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. In patients with an acquired connective tissue disorder (e.g.,lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted towards a diagnosis of hEDS in this situation.
    3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses and diagnostic categories include, but are not limited to, neuromuscular disorders (e.g.,myopathic EDS, Bethlem myopathy), other hereditary disorders of connective tissue (e.g.,other types of EDS, Loeys-Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g.,OI). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.
    https://ehlers-danlos.com/wp-content/uploads/hEDSvHSD.pdf (formatting mostly copied from here)

    Hypermobility Spectrum Disorder is the catch-all term for people who don't fit into hEDS, but it's expected that this will be divided into new diseases. As research is continuing to find more types of EDS as well as other things that may be going wrong, this is a reasonable expectation in my view.


    refs (not intended to imply I read any part that is not freely available)
    Last edited: May 27, 2019
  10. WillowJ

    WillowJ Senior Member (Voting Rights)

    I understand that you were discussing your own paper, but regardless of who wrote it, a criticism needs to be specific in order to be of any use.

    I am not entirely sure why you are criticising the design "try to prove we were wrong about x."

    Regarding valve things, this is what I can find about the current state of the science (2017, formatted to add paragraph breaks and adjust spacing):

    Mitral valve prolapse (MVP) was previously considered a common feature of EDS and many other HCTDs, but that was prior to the establishment of more rigorous criteria for the diagnosis of MVP.

    Since then, some studies show no increase in the frequency of clinically significant MVP [Dolan et al., 1997,McDonnell et al., 2006, Atzinger et al.,2011] and others show an MVP frequency of 28–67% among hEDS patients [Camerota et al., 2014; Kozanogluet al., 2016]. Increased prevalence of mitral and tricuspid insufficiency has also been reported [Camerota et al.,2014].

    Since the mitral valve relies upon collagen for its tensile strength, and myxomatous MVP is characterized by disruption of the collagen layer with expansion of glycosaminoglycans within the middle layer of the valve [Dellingand Vasan, 2014], it is reasonable to still consider MVP as a potential clue for hEDS, but the true clinical significance is not yet known.​

    full text available at https://www.ehlers-danlos.com/pdf/2...tics_Part_C-_Seminars_in_Medical_Genetics.pdf

    Seems a reasonable assessment to me. I didn't read the individual papers, but the summary doesn't raise any flags.
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  11. Milo

    Milo Senior Member (Voting Rights)

    I simply think we have to be cautious in linking all kinds of conditions together and assuming they are all related. Interestingly there is a chatter on Facebook in a Lyme group that Lyme and CCI is related. This is absolutely crazy and hard to link scientifically.

    The line of thinking as i understood it was like (and i may be wrong):
    - I have ME
    - I had a surgical procedure on my thyroid and was subsequently diagnosed with CCI
    - CCI is prevalent with EDS.
    - therefore EDS is lilely prevalent with ME

    This in my opinion is a logic problem.(I remember my philosophy courses very well). Jen has shared her experience, and there has been a few more. Nothing wrong to share N=1 experience. However in my opinion and since we are all about science in this forum, we do need actual science and research to truly look into cause and effects of N=1 experiences, find biomarkers for each condition, and have the whole scientific community agreeing in these standards.

    If we look back into history, we have been there before. The XMRV thing. ‘It’s the retrovirus, stupid.’ People to this day are still taking anti-retrovirals to treat ME and some claim it helps them. We have no way to decide whether the patient had a strong placebo response or an anti-inflammatory response or what.

    We need biomarkers. And subsets. And careful dignosis. Patients deserve access to competent and thorough work up/diagnosis.
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  12. WillowJ

    WillowJ Senior Member (Voting Rights)

    I agree with this.

    and I also agree that one should be cautious generalizing from a handful of cases to all of ME.

    Just one also would do well to be cautious saying some other diagnosis is "contested" (people might read "bogus"). ME isn't the only disease that has a lack of access to medical care, and in my view it would be better to collaborate with other such diseases to gain access for all neglected diseases.

    It's true that the diagnosis for hEDS is clinical, but so is the diagnosis for ME. Lupus had a clinical diagnosis at one point. That's what happens when you can't find a microbial marker that meets Koch's postulates and/or don't have another type of biomarker yet, but still need to make a diagnosis.

    Exactly. All patients.
  13. sb4

    sb4 Senior Member (Voting Rights)

    I don't think Lyme and CCI is necessarily any more difficult to link than CFS and CCI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751012/

    That study shows Lyme damages collagen. Pathogens associated with CFS also may damage collagen.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    I don't really want to plough through issues of hypermobility but I think it needs to be thought through because of the concerns about it being the basis of ideas that may lead people to have inappropriate surgery.

    I was talking about working with Rodney Grahame in 1979 - long before Rodney went to Brighton.

    The real issue is what does 'best practice' mean.

    Beighton is crummy because the presence of mild hypermobility in several places has little to do with significant hypermobility in one or two places causing things like shoulder dislocation - which is often a local problem. But as you say at least Beighton is based on a single concept - hypermobility - and tries to measure that.

    What I see now as criteria for 'hEDS' look to be very badly thought out - and that is sadly what I would expect in this field.

    I think everyone involved in the genetic side will assume that hEDS will cover a cluster of polygenic conditions. If they were Mendelian monogenic conditions they would have been tracked down.

    If you are looking for a member of a cluster of conditions there is no reason to think any particular criteria will identify any of these conditions best. The criteria may be useful for classification in research but it tells us nothing useful about an individual person. It does not tell us the cause of their problem because we do not know the cause of any form of hEDS.

    There is then the problem that the criteria add in symptoms. Symptoms are subjective and their inclusion leads to expectation bias. The inclusion of symptoms suggests that someone lucky enough to have the underlying connective tissue problem who has not yet got symptoms cannot be said to have the underlying connective tissue problem 'hEDS'. There is a category confusion. This sort of category confusion is what has dogged the field from the 1970s.

    There is also the problem that if these are polygenic conditions they are likely to be very often sporadic so requiring a family history is illogical.

    There are also inclusions like velvety skin and Marfanoid habitus which in my experience are so subjective that they allow the physician to tick the box for almost everyone.

    In simple terms there is no scientific basis for this set of criteria. It is stamp collecting.
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  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    Proving one is wrong about x is fine. That is not what I was talking about. What I was talking about is proving something that contradicts a premise of the hypothesis being proven.

    The hypothesis was that people defined as having no laxity in any internal organ beyond joints have laxity in their heart valves. That is a contradiction. If people with BHS have mitral valve prolapse the definition of BHS is invalid. That then begs the question of what defined the cohort of people in the study if it was not BHS. The answer is that they were defined by having pitched up at a particular clinic and had a Beighton Score of maybe 6 or more (I forget) and no barn door evidence of other problems.

    To publish a paper saying that people with no internal organ problems have internal organ problems is just silly. This dawned on me about half way through the project.
  16. Lucibee

    Lucibee Senior Member (Voting Rights)

  17. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    Somebody did. My comments are on the CCI thread I think.

    It would be good to have a new paper on prevalence but I doubt the 1/5000 figure is that far off.

    I would urge Emma to look at the wording of the toolkit and clarify it. The old joint hypermobility syndrome is definitely not a subset of hEDS.
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  18. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    London, UK
    Apparently the self reported rate of EDS in the recent UKBiobank study of 350,000 people was 1/4000 - not too far off 1/5000.
  19. WillowJ

    WillowJ Senior Member (Voting Rights)

    I think that
    1) if there are researchers and clinicians active in the field who think it's a worthwhile field and are being respectful of patients and
    2) the patients are endorsing the criteria (even better, being included, but at least endorsing the result)
    and 3) the criteria is managing evidence honestly (even if the evidence is, due to poor funding, not enough diagnosis, etc., not very prolific)

    that it's safe to say that the resulting criteria is "best practice".

    Not necessarily (on either point)

    It's counter-intuitive but it actually takes bigger and longer studies to find common genes than rare genes. I am not at all certain that even one large and long enough study has been conducted in this area. I have posted a study in the research section dealing with the largeness of studies needed and will try to edit with that thread.

    EDS is typically inherited in a pattern that appears to be autosomal dominant. This is a Mendelain inheritance pattern. It could be that the problem is that, while it's possible there may be more than one condition collected in hEDS and certainly it's guessed that there's more than one in hypermobility spectrum disorders (HSD), these conditions are either too common to find without exorbitantly large studies, or the genes are something unexpected (maybe don't deal with collagen directly--some of the other discovered genes for the rarer EDS variants don't, and no one has discovered what the connection is). [ideas not original to me, but I don't have a citation handy]

    It also could be that there are non-genetic factors influencing gene expression (the inheritance is still autosomal dominant in a lot of cases). Or there could be oligenetic or polygenetic genes at least in some cases. https://www.ehlers-danlos.com/pdf/2...tics_Part_C-_Seminars_in_Medical_Genetics.pdf

    No one is ruling anything out at this point, which is as it should be.
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  20. WillowJ

    WillowJ Senior Member (Voting Rights)

    This is obviously not occurring, as people are not getting diagnosed. Non-diagnosis is the biggest diagnostic challenge right now.

    You can't really go off a self-report rate in a disease where people are not getting diagnosed and are unlikely to suspect they have it unless they have a relative diagnosed or are very good at researching to find their own diagnosis.

    It's not like "chronic fatigue syndrome" where a nonspecific symptom is referenced and people will say "oh I have that" even if they are not ill at all, or if they're undiagnosed with some other disease, or even diagnosed and their doctor didn't explain (or didn't realize) that their other condition can cause a large amount of fatigue.

    From the paper referenced in my above post:
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