The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Could CFS/ME be a vasculitis?

Discussion in 'General ME/CFS Discussion' started by dan062, Nov 17, 2014.

  1. dan062

    dan062 Senior Member

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    I've been wondering this for a while so thought I'd put it out for consideration to the group. I'd be particularly interested to hear from @Jonathan Edwards and any other residents doctors / retired doctors we have in our midst.

    I spent a lot of (pointless) time the past year looking for a diagnosis that fit my symptoms - I'm sure a lot of us have. One I kept coming back to was the various vasculidities but I ultimately concluded that given their rarity and a with (in my case) a normal ESR, CRP, WCC and no hematuria that it was highly improbable.

    Nevertheless, of all the strange diseases I've been looking at, vasculitis seemed (to my un-medical brain) to fit the CFS/ME bill the best. (There's one other blog post on the net that wonders this also).

    This does nothing, of course, for treatment (unless we can managed to get diagnosed) but I wanted to see if anyone else thought the hypothesis was credible.

    Reasoning for:

    • CFS/ME is characterized by three key dysfunctions: neurological, circulatory/cardiovascular and immunological. Vasculitis can easily explain the first two through recurrent ischemic damage to the brain stem (or other parts of the brain) and the heart; as an autoimmune disease, I presume that dysfunctional immunity would be expected.
    • The pathogenesis of the vasculidities seems something of a mystery, but viral infections seem to be implicated in the majority of cases (this is true, of course, of many other autoimmune diseases).
    • Although unlikely, vasculitis occasionally can have normal inflammatory markers (example case report), but most doctors will follow the rule that 99% of the time a normal ESR strongly argues against the diagnosis and mark it off the differential. In such a situation, it would seem highly unlikely that any doctor would risk performing a blood vessel biopsy.
    • The success of the rituximab trials would be consistent with CFS/ME being a vasculitis.
    • Many of us report symptoms such as chronic sinusitis, prostatitis, etc, which would be consistent with vasculitis.
    Reasoning against:

    • Our generally normal inflammatory markers.
    • Generally, we lack major renal or liver disease (however not all vasculidities attack these organs) and chest x-rays are also normal.
    • Supposed rarity of vasculidities (although perhaps, given the 'protean nature' of their presentations, perhaps they are underdiagnosed?).
    • We also lack major vasculitic skin findings. Although some of the things many of us report (such as bier spots) could seem consistent with a vasculitic process.
    I know that most of the twenty or so vasculidities have specific findings (e.g. mouth ulcers in Behcet's; absent pulses in Takayasu's). The idea I'm putting out isn't so much that a subset of CFS/ME is an undiagnosed form of an established vasculitis so much as that perhaps it is one which hasn't been recognized as such yet.

    Maybe this might only apply to a subset of patients, but perhaps CFS/ME being a subclinical (or undiagnosed) systemic vasculitis could be an explanation for some.
     
    Last edited: Nov 18, 2014
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  2. dan062

    dan062 Senior Member

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    Follow up question:

    Perhaps as a follow on to the above, someone could explain the significance of ESR/CRP in ruling out things like this for us.

    It seems as if someone with ANA + ESR will be considered for lupus/Sjogrens but with just one of those they fall back on CFS/ME.

    Same for RA/vasculitis etc.

    Is it really a fool-proof measure of inflammation if there are documented cases where it's been proven wrong?)
     
    Last edited: Nov 18, 2014
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  3. duncan

    duncan Senior Member

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    I have suggested this for myself as I have a couple MRI's which demonstrate mild brain atrophy. I have tried to get SPECT scans to look at blood flow, to see if it could be due to something like Lyme vasculitis, or some other vasculitus behind the atrophy and multiple foci, but to no avail. It is next to impossible to get SPECT scans in the US.
     
  4. Matthew Jones

    Matthew Jones Senior Member

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    I had a cerebral venogram near the start of my illness and they found a minor narrowing of the veins in my neck, but at the time I was on an upswing from cutting out gluten and told them I thought I was getting better so don't bother looking into it (but quickly relapseD). Almost 4 years later I'm getting the scan re-done. I never heard them use the term 'vasculitis' but it sounds similar...
     
  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    These are reasonable questions dan062, but I think we can cross vasculitis off our is for a very simple structural reason, which I will come to.

    It does seem irrational the way doctors diagnose diseases with a bit of this test and a bit of that and not a bit of the other, but at the end of the day it does all add up. I think it may be a bit like going round Cruft's dog show for the first time. You may ask why one dog is an Irish Setter and another an Irish Wolfhound, or one a King Charles and another a Cocker Spaniel. You will get the reply that the ears are a bit longer and the legs a bit shorter and.... and... . And so it is with lupus and RA and Wegener's etc. And there are mongrel diseases, which there are for dogs but not at Crufts, but we can still recognise where they fit.

    What we now understand is that all these different patterns of disease can be related to different molecular or cellular structures. For instance RA is a disease of very small immune complexes. Lupus has all sizes of complexes so has a wider span. A subgroup of vasculitides have vessel damage because of interactions between antibody and circulating neutrophils etc. etc.

    The reason why I think we can exclude vasculitis is that vasculitis implies inflammatory damage to a vessel wall causing significant structural disruption (not just leaking a bit more fluid as in nettle rash). Even damage to very small vessels tends to produce cell infiltration over a distance of about a millimetre minimum. Nailfold vasculitis in RA gives brown marks about 2mm long. Most other vasculitides produce bigger lesions. The exception may be glomerular damage in the kidney, where cells do not get beyond Bowman's capsule, which is probably less than 1mm across.

    Lesions of 1mm can be seen, either on skin or mucosa, or on biopsy. A single vasculitic lesion in the brainstem is very likely to make you unconscious or at least have gross neurological signs. So just for this reason I think we can exclude vasculitis in ME because if it is there it is findable. ME seems pretty certain to be due to some abnormality that does not alter structure in such a direct way. It has gone under the radar because it is a change at a more subtle, maybe immunochemical level.

    Another point is that vasculitis is not itself a disease or even a group of diseases. It is a particular type of lesion that can occur as part of a huge range of diseases of all sorts of causes, from poisons to viruses to bacteria to autoantibodies to goodness knows what. Wegener's granulomatosis is often classified as a vasculitis but in fact the granulomas do not show much in the way of vasculitis - it is just that vasculitis elsewhere is part of the disease complex. There are also several major different types of vasculitic lesions - some in capillaries, some in venules, some in arteries, some in glomeruli, and they can be quite different in the sorts of cells that cause damage.
     
  6. snowathlete

    snowathlete

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    But wait, there is I think, some visible vascular damage in ME/CFS. See this thread on petchia - doesn't that support Dan's suggestion of some kind of vasculitis, though probably not in the brain stem, @Jonathan Edwards ?
     
    Last edited: Nov 17, 2014
  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Skin petechia are not necessarily abnormal. Everyone has a few from time to time. If you biopsy ordinary petechia you will see red cells leaking from a vessel but not a white cell infiltrate causing the leak. Petechia are a limited version of purpura, where red cells leak out of vessels. In vasculitis purpura is associated with an inflammatory reaction which makes the red/blue patch raised and is often referred to as 'palpable purpura'. And the palpable lump is not just the bruise itself but solid white cells.

    It is always possible to hypothesise a lesion that is just on the verge of a true vasculitis that might look like ordinary petechiae but I think it would have been picked up. In the days when physicians prided themselves on recognising strange signs they got good at recognising much rare disease than ME. I don't think I am going to buy it!
     
  8. dan062

    dan062 Senior Member

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    Thanks so much, @Jonathan Edwards - fantastic reply!

    This is exactly the sort of information I wish doctors had time to explain to us (I think an 'Ask the Consultant' book would be a fascinating project if you're ever thinking about authorship).

    I'm very much aware that while the internet can (occasionally) provide us with useful information about a possible diagnosis, or further testing to explore with our doctors, that without the years of underlying medical knowledge actual doctors have we're seeing things without all the relevant context.

    @snowathlete I think @Jonathan Edwards 's point (if I'm understanding correctly) is that vasculitic changes can be seen in a huge variety of diseases.

    I don't think his answer necessarily precludes the idea that there could be some vascular damage as part of ME/CFS (I think that's been established already, no?), just that it would be nowhere near severe enough for it to be a kind of abortive or undiagnosed form of primary systemic vasculitis, I was naively implying.

    Such a process would obviously raise the inflammatory markers and produce skin lesions that might that diagnosis obvious to any rheumatologist, etc.
     
  9. dan062

    dan062 Senior Member

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    I didn't realize this was the trend.

    I think a lot of us assume that if we have a rare disease in our own minds (even just vasculitis kind of rare) that our doctors. especially in primary care, aren't going to have contemplated it.

    I find it kind of amazing that that's not the case. I asked about two weird ones recently (Wilson's and Moyamoya -- really, really rare!) and was amazed that my PCP was able to explain why both weren't possibilities (normal LFTs and brain MRI respectively).

    We might be familiar with a small subset of possibilities (neuro ones, primarily) but a PCP/GP has to know pretty much everything I guess. How many diseases and workups can a person hold in their memory?
     
  10. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Primary care doctors may not have such a wide mental library for skin lesions but a good dermatologist will instantly recognise any of over a hundred conditions. If ME included true vasculitic lesions some physician with a special interest in 'neuraesthenia' or whatever it was called a hundred years ago would have written a paper on it. All doctors know about Campbell de Morgan spots, spider naevi, pityriasis rosea and versicolor (an even varicelliformis) and so on, even though most of them are of no great importance. It is a bit like trainspotting.
     
  11. WillowJ

    WillowJ คภภเє ɠรค๓թєl

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    back to the brain, though, what is meant by "gross neurologic signs"? Just the stuff they test for at the neurologist at an initial consult? (The main one of those a good proportion of ME patients are said in the literature to fail is Romborg or tandem Romborg.) And do they have to be the same all the time, or can they be transient?

    What could explain neurologic signs (and symptoms) that are transient, time-limited, or change from time to time?

    Gait changes, vision problems (like blacking out or blurry spots), grasp problems, balance problems, seizing episodes, slurred or stuttering speech, difficulty understanding or speaking language, stiff face...

    such things are well known among the moderate/severe and severe patients, but we cannot always get to doctors, or we do go and they don't care because it doesn't seem to fit a diagnostic box they can think of, or they didn't actually pay attention because we already had a CFS label (or even without it, they thought something was odd about our case: we were too young, our HR was too high so they had it all down to anxiety, we "seemed fine" , whatever). So it doesn't really make the literature today.

    This is not so different from severe forms of migraine, which includes some amount of vascular damage in the brain. Both migraine and ME can cause punctate lesions?
     
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  12. ukxmrv

    ukxmrv Senior Member

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    ""The only abnormalities discovered by Pellew and Miles (1955) were minute red spots along the course of the sciatic nerves. Under the microscope the red spots contained localised collections of inflammatory cells, which had also infiltrated the area where the nerve roots come out of the spinal cord. The red colour of the spots was due to leakage of red blood cells.

    ME/NM is very rarely fatal so that a post-mortem study showing similar haemorrhages in humans is unique. However, during the North of England epidemic in 1955 Andrew Wallis described the findings in a patient in her fifties, who developed the characteristic febrile illness leaving her debilitated and emotional (10). During the next fifteen months she continued to run a low grade fever with continued mental deterioration before she died. The post-mortem revealed numerous small haemorrhages around blood vessels in the cerebral cortex extending into the mid-brain, which were considered to be the cause of her death. These abnormalities may be found when patients die as the result of severe chronic alcoholism. This was not a factor in her case; she had had a febrile illness.

    Vasculitis involving the skin was recorded during outbreaks in Cumberland, Durham and North West London in 1955. A maculopapular rash may appear during the return of features of the initial illness such as flu-like symptoms and enlargement of lymph glands and liver. This skin overlying areas of localised muscle weakness may be affected at the time of these attacks.""

    http://www.meresearch.org.uk/information/publications/acheson-review/
     
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  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    When I say that a vasculitic lesion in the brain stem would produce gross neurological signs I am thinking of loss of consciousness, maybe inability to move one leg, or one side of the face drooping, or at minimum some change in the reflexes like being brisk on one side or a positive Babinski sign in a big toe. I would expect the signs to last for at least a week and more likely months even if there was recovery. Further episodes of vasculitis would produce different signs each time. All the examples you give, WillowJ, are symptoms and some of them could occur with a brainstem lesion but if it was vasculitis there would be signs for a neurologist to pick up independent of symptoms.

    Migraine per se does not cause vascular damage. It is an episode of vascular dilatation without damage to the wall of the vessel and would not cause punctate lesions.

    Both WillowJ and ukxmrv rightly point out that there are cases diagnosed as ME who do have punctate lesions that may be consistent with vasculitis, including at least one case associated with an epidemic. The problem here is that we already recognise that viral encephalitis can involve vasculitis and if that vasculitis did not hit the brain stem or spinal cord directly the illness could look like 'ME' and it would be fair to say that it was ME, although of a rather unusual form leading to progressive neurological failure and death. However, what does not seem very likely is that the great majority of PWME have symptoms because of vaculitis. They could well have symptoms because of a lower level vascular lesion without damage to the vessel wall though. It is also possible that what seem like brain stem problems are actually due to mild vasculitis lesions somewhere else, like in the cerebral cortex, but people with widespread cerebrovascular lesions for other reasons do not generally develop an illness like ME.

    I agree that everything is just about possible. However, my thought is that rather than going looking for vasculitic lesions in the majority of PWME when there are lots of reasons for thinking we will not find them, it is probably more sensible to go looking for more subtle changes, which may be vascular, that might show up on PET or fMRI scans. We now have two recent studies showing abnormalities on such scans that look to be well worth confirming.

    And I come back to the fact that even in the disease often called 'vasculitides' the vasculitis is often only one component of a more widespread disease. Lupus is interesting because it can give vascular lesions ranging from the most subtle tendency to leak plasma to outright vessel destruction. I would put my money on any brain changes in most PWME being more like the former. We might still be looking for 'microvascular pathology' and associated with autoimmunity but I think to call it vasculitis may be a red herring.
     
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  14. dan062

    dan062 Senior Member

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    @ukxmrv I seem to have forgotten when I was proposing my idea that cerebral vasculitis is very serious stuff as @Jonathan Edwards is saying.

    I think the same could be said for encephalitis. If you read the non specific symptom list it initially seems as if it could fit the bill, but even if ME/CFS does feature some degree of encephalitis in its pathology (which, again, I think it's accepted to), the degree of severity between it and what is conventionally called encaphalitis entails (with stuff like comas, personality loss, etc) is vast in most cases.

    Also, if any of you have also had basic brain imaging (a regular MRI, not a SPECT) then major cereberal vasculitis would definitely have shown up.

    I'm sorry I forgot all this before I posted, but I do think it would be interesting to see if microvascular abnormalities are shown to be part of the disease process once that is studied.
     
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  15. melamine

    melamine Senior Member

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    This is the best explanation I have seen so far for my own situation, that I too thought might relate to some kind of vasculitis. Modest lab evidence of autoimmunity, symptoms and symptom exacerbation profile, and some HLA testing supported the possibility of an autoimmune condition of some rarer type that fit imperfectly with some of the vasculatides as much as with lupus, for instance. However, I too eventually concluded that it was not the most useful approach, believing instead that some kind of more generalized autoimmune process may be at work secondary to immune deficiency and associated infections, as well as hypersensitivity reactions. If there is vascular pathology in my case, my belief is that it is probably not in the driver's seat.
     
  16. dan062

    dan062 Senior Member

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    @melamine I think your explanation could apply to so many of us whose conditions are possibly a jumble of infections, possibly autoimmunity (as a consequence, or possibly the cause), all in different shades of grey, that slip between and around the various clearer diagnoses in their more classic presentations.

    My concern has always just been that if that's the case, why not treat us anyway? I can't understand why everything has to fit a box when doctors' own understanding of disease (Th1, Th2 inflammatory states, etc) shows that pathology just doesn't behave like that, and all sort of overlap and incomplete syndromes are possible.

    I find @Jonathan Edwards' explanations very helpful as well. Once you understand things like these it makes the whole process of diagnosis a lot less bewildering -- if still no less frustrating.
     
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  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    It's been an interesting discussion. There is never any harm in going through arguments for things to make sure they really add up like this. And we are all reminded that there are loose ends - as you say. A lot of people like Charles Shepherd would say that Ramsay was a bit over the top to call it myalgic encephalomyel-itis, but then some of the original epidemic cases may have had frank encephalitis. I have no doubt there is an encephalopathy of a sort.
     
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  18. WillowJ

    WillowJ คภภเє ɠรค๓թєl

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    Thanks. :) That's what I was thinking, too!

    Migraine, though, is one of the causes discussed by a neurologist as a possible cause for my lesions.
    Small abstract: http://www.ncbi.nlm.nih.gov/pubmed/1399549

    Larger study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241741/
    They suspect hypoperfusion as a cause, among other things. Maybe this is why I experience migraine aura and ME so similarly.
     
    Last edited: Nov 19, 2014
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  19. duncan

    duncan Senior Member

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    I think that very few of us would suggest that ME/CFS is a static condition. The fact that so many begin with an acute illness, usually involving a febrile element, gives testimony that this disease presents differently, not just among individuals, but within a single patient over time.

    With that in mind, I don't think it's too outrageous to suggest that early onset ME/CFS may involve vasculitis, including cerebellar vasculitis. That acute condition could involve the 7th cranial nerve (facial drooping) or the 8th (vertigo, dizziness), or any other part of the brain for that matter. This possibly could also be when the "itis" ME component would be most overt, most pronounced, and arguable most observable. Problem is, few clinicians think to look because I would wager even with acute cases, often symptoms are either too transitory or muted or take the back seat to other symptoms. Once the infection has left the acute phase, the disease progresses - ratchets down in terms of common labs/tests? - to chronic levels which are even harder to clinically evaluate. At this point the patient is left to deal with a slow burning process that is never fully extinguished. For some, too, there is permanent damage, residual damage, left in the wake of the acute process.

    Sorry, long winded way to suggest maybe vasculitis is part of the problem for some ME/CFSers, but that it resolves early on, leaving behind tracks that are ambiguous at best, even when a savvy neurologist is involved.
     
    Last edited: Nov 19, 2014
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  20. melamine

    melamine Senior Member

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    @ duncan - my illness did in fact begin with an acute mono infection with symptoms of encephalitis - ataxia, headache and light sensitivity. Being young and away from friends and family at the time and feeling too sick to go to an ER alone, I stuck it out. Had I not, I would probably have gotten a retrospectively life-altering for the better Dx. One of the residual symptoms besides post viral CFS, was loss of much of my episodic memory.

    During another severe infection in 2007 I experienced a different kind of brain symptom - felt literally, like there was a hole in the middle of my brain and all thoughts had to connect around it. It was very disturbing. It too left me with residual memory problems of a different sort, as well as increased executive dysfunction and a progressing neuropathic condition, which, however, clues before the infection were minimal but present for about 7 years.
     

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