The science of craniocervical instability and other spinal issues and their possible connection with ME/CFS - discussion thread

First of all, we're talking about subsets of patients, secondly, physicians have long had selective vision and focused on the symptoms they want to see to validate their view of a particular disease. Patients play along by hitting the right notes (agreeing with the right words) so that they can get their diagnosis and treatment.

Those physicians who actually bothered to listen no doubt thought it is interesting that their patients somehow provide a quite different picture to what is presented in the 'mainstream' medical literature. Many of them quietly dismissed their concerns as their additional observations did not actually lead to any foreseeable change in their medical practise.

This sort of bias in neurologists has historically been very common - the dismissal of all symptoms as unimportant except those which there is strong consensus as being caused by a specific lesion. You know exactly what I am talking about here!

So a new generation of physicians claim to have identified a new pattern and are attempting to form a new consensus. It is irresponsible to dismiss this a priori, but instead we need to do the experiments and gather data as we always have done when new contradictions emerge.

My opinion is I find it unlikely that most ME or CFS cases are caused by this, but regardless of how rare this coincidence may be, it seems there are a few people who have CFS-like symptoms and are misdiagnosed - until they later develop more severe symptoms that you would expect of this syndrome - ataxia, breathing regulation, certain types of tremor and related issues.

The problem of course is that ME (*non-Ramsay) and CFS definitions are non-specific and primarily exclusionary. If diagnoses are missed/overlooked, then misdiagnosis is not uncommon.

 

This is known as anchoring bias.
Here is an interesting podcast about it, nothing about ME or CCI though
https://figure1.com/ddx/episode-2/

 

I am not dismissing a priori but I am pointing out reasons why we should be very sceptical.

This is not a new generation of physicians. The 'consensus statement' is not a formally published academic statement from the profession. It is a statement from a 'think-tank' meeting of surgeons organised by the Chiari and Syringomyelia Foundation. The document (which Michiel cites) includes a lot of loose language including the suggestion that CCI is a common problem.

I agree with you that the medical profession can think in tramlines. But I just find it completely implausible that those of us who looked after people with CCI missed the fact that they had ME-like symptoms. I met people with ME symptoms but none of the people I looked after with CCI had anything resembling ME. The had numb hands and stiff legs and neck pain.

If you look at the description of cervical medullary syndrome in that statement you could actually come to the conclusion that everybody and nobody has it. There are no specific requirements. I can only find two references to the statement on Google. One is Henderson's paper. The other is a news article about CCI surgery in Spain.

The other thing I keep coming back to is that this syndrome arose in the context of Chiari but seems to be being applied to CCI. Chiari and CCI may be related in the specific context of developmental disorders, but they are different things. This sort of 'now it this and now it is that' aspect of the story to me is a standard red flag for muddled thinking.

 

I agree with being very sceptical.

The first question one asks oneself is whether this is misdiagnosis of another condition as ME or whether ME causes neck trouble.

For the reasons you mention @Jonathan Edwards there is a case for saying these conditions should not easily be mistaken for each other, which favours the idea that PWME have been diagnosed with additional neck problems.

But on the other hand ME is a bucket diagnosis and its possible to believe people who did not meet the appropriate specialist, who could recognise their real condition, could end up in a muddle with the wrong diagnosis.

Another alternative from the sceptical perspective is that some specialists are so engrossed with their speciality that they see it wherever they look and are overdiagnosing susceptible ME patients, while patients who undergo an irreversible procedure costing €70k are under some pressure to believe and justify that it was the right thing to do.

Sitting on the sidelines its is not easy to know what is really going on. Though I do have sympathy with the idea of the neck as a weakness for ME patients, because to be honest I have experienced an apparent weakening of my neck since the beginning of ME. But that as they say is a long story.

i.e. in my case ME onset was after EBV and concurrent with the start of recurring HSV2 and caused among other things a big problem with inability to stand up without losing blood supply to the head, which at one point, standing up when doing yoga in my digs, caused me to faint and keel over and I woke up to find a big dent in the rolled steel structure of a twin bar electric fire and a gash on my head, suggesting they may have collided with some force, coupled to which the room was spinning as it were. So I always wonder if that was a contributor to later difficulty with tipping my head back which I now have, or whether it was more of the ME and another manifestation of something like palindromic rheumatism which has been a consistent but ever shifting feature of my condition affecting different symmetrical pairs of joints over the course of several years each but with a particular preference for causing shoulder ball joint pain and TMJ. Though I am certain by the historical sequence that ME CFIDS came first I cannot rule out injury in my case.

I have heard of other PWME who have problems with swallowing, which indicates some difficulty with muscle strength and autonomic reflexes in the neck as well as previously mentioned science in relation to brainstem and cranial blood flow and inflammation.

I feel I dont know what is going on and it is not impossible that different things are going on for different patients having this procedure, who only superficially resemble each other. The inevitable conclusion being, yet again, that until we can get reliable diagnosis, preferrably molecular subtyping, we are shadow boxing. But I wish all those concerned well and sincerely hope their outcomes are beneficial.

 

This came up in my google search this morning. Lady has EDS (Types 1 and 12) and CFS (purportedly due to the EDS) and now thinks she has CCI. Her partner's mother has put up a GoFundMe page to try and raise the money for the CCI surgery. Most of the meat of the article is summarised in the video at the start (you might want to turn the volume down on your computer as it's accompanied by annoying music).

@Jonathan Edwards I thought you might find it interesting, though it's not the easiest of viewing and reading (in terms of how it's laid out)! But it does seem to me that your worries about fashionable surgery might be supported by this article. Please forgive me if I've mis-understood your stance on this.

 

Here's a less medical input. A good friend of mine from our local ME support group has just undergone such surgery in Barcelona. The transformation so far has been spectacular, although of course it is early days.

In that context I'd like to make two points.

The first is that many people who hand out diagnoses of ME aren't that reliable. I look at the studies from London and Newcastle and note that on average only around half the people sent to them have ME: the rest have something that has been missed. But both of those centres use extensive testing. In our area in Sussex, diagnosis was a matter of a 15 or 20 minute chat, and a chunk of that was simply confirming basic details (name etc.), before a diagnosis of ME was made, then being handed on to a therapy team, never to see a specialist again. I know people often quote 250,000 people in the UK with ME: my personal view is that I wouldn't be at all surprised if only half of them turn out to have ME, and that the rest were misdiagnosed.

The second is that I understand there are 13 different types of EDS, mostly genetic. Obviously there are going to be people with EDS who develop other conditions, including ME, before the deteriorating EDS effects start to kick in. If these patients have already been given a diagnosis of ME, it is so easy just to go along with that, and not spot that something different is happening. By the time a diagnosis of EDS is made (if it is), the patient has interpreted most of the symptoms through the ME filter.

In our group of around 30 people with a diagnosis of ME, three now have a diagnosis of EDS, and in all three cases there is clear genetic transfer to their children. Do they have ME? Did they have ME? Does the underlying EDS leave folk more vulnerable to ME. It's very hard to say. But when the topic originally arose a few years back, these were the three whose patterns of symptoms were subtly different to the rest of us. It's hard to be really specific about overall impressions, but broadly speaking, all three showed steady deterioration, much more that the rest of us, and, perhaps more importantly, their physical deterioration was more significant than their "mental" deterioration. Two of them did have a sudden-onset form of ME.

I did enquire about the position of such surgery in the UK in the NHS. They carry out around 6000 such operation per year, but only half-a-dozen on people with EDS. I haven't been able to find out any more details. We are in the hands of a small number of specialists making assertive statements: it is difficult to get clear information: now where have we seen that happen before?

 

Except that it also says that it is a disc - which is not CCI. And we are not told what is supposed to be the effect of the disc. Confusion as before.

 

It does seem implausible. But what if the CCI/AAI only appears a little later in the course of the ME/CFS disease, as a consequence of ME/CFS? Once patients receive the ME/CFS diagnosis, they probably are not going to get much further medical attention in terms of MRIs etc.


How could ME/CFS create a CCI/AAI?

My own speculative hypothesis is that because infections such as enterovirus can induce a set of enzymes called matrix metalloproteinases (MMPs) which break down connective tissue, and given that ME/CFS brain autopsies have found chronic enterovirus infection in the brainstem, perhaps this infection weakens the ligaments holding the C1 atlas vertebra to the skull, thus leading to CCI/AAI and brainstem compression.

In this hypothesis, the development of CCI/AAI would be a consequence of contracting an ME/CFS virus like enterovirus. But once CCI/AAI and brainstem compression have appeared in this way, it is possible the compression plays a role in maintaining the infection and maintaining ME/CFS, by causing autonomic nervous system dysfunction, which may prevent viral clearance, and/or which may cause a dysfunctional immune response, or autoimmune response.

I understand there is increasing research showing a complex interaction between the immune system and the autonomic nervous system.

Interestingly, the research of Dr David Systrom has led him to suspect that ME/CFS may be underpinned and maintained by autonomic nervous system dysfunction or imbalance (see timecode 25:50 of this video interview of Dr Systrom).



Thus if we go with this hypothesis for a minute, and assume ME/CFS is in essence caused by autonomic imbalance or dysfunction, then it suggests these CCI/AAI cases do have regular ME/CFS, but the cause of the autonomic dysfunction may be unusual: brainstem compression (although just how large a subset these CCI/AAI cases comprise remains to be seen).

But taking this hypothesis further: if autonomic dysfunction were indeed the underlying cause of ME/CFS, what is creating the autonomic dysfunction in non-CCI/AAI ME/CFS patients?

The first idea that springs to my mind is perhaps the dorsal root ganglia (DRG) inflammation which has been found in the autopsies of several ME/CFS patients. I am not entirely sure, and I will have to check, but I think the afferent (sensory) part of the sympathetic nerves will route through the DRG. Thus the DRG inflammation may alter sympathetic functioning.

We also know that enterovirus can infect and travel along the vagus and enter the brainstem, and possibly this may alter parasympathetic functioning

 

If ME was capable of eroding ligament insertions in such a way as to produce laxity there would be severe cases from history with overt CCI and tetraplegia with specimens in the path museum. There is not the slightest hint of any pathology of that kind.

I get the impression that some people have been led to believe that ligamentous laxity might develop newly in people with EDS or ME as a result of some progressive process. In EDS the laxity develops during growth and then remains as it is. In ME we do not have any evidence of newly developed laxity anywhere - other than secondary to knee joints wearing with age maybe.

New development of laxity occurs in RA as a result of erosion of the insertion of the ligament into bone or rupture of the ligament. But the inflammatory process that causes this is gross and easily seen pathologically.

 

An important point.

 

I am not able to focus on the thread just now but just a quick point for @Graham.

The prevalence of EDS is usually said to be 1/5000 by geneticists. However, 'hyper mobile EDS' is a diagnosis given by rheumatologists and pain specialists and only requires hypermobility and chronic pain and/or fatigue. Hypermobility occurs in ~10% of the population.

Now if we do the maths we see that we expect 10% (3 of 30) people with chronic pain and/or fatigue (which PWME will likely qualify for) to qualify for 'hEDS'. But that does not mean that their hypermobility actually has anything to dow tih their pain or fatigue - because the prevalence of hypermobility is just the same as normal. If 1/500 have ME then we expect 1/5000 to have 'hEDS'. That seems to use up all the EDS but the figures are not going to be exact. hEDS is almost certainly the commonest form but I suspect most geneticists would not count it as proven EDS.

So EDS in 10% of PWME is not really the same thing as the sort of EDS the lady in ladycatlover's article has. The latter sort of EDS is pretty easy to diagnose as you can see from the pictures. hEDS is pretty easy to diagnose but a lot of physicians, like myself, would not think it was necessarily a helpful diagnosis since we do not have any reason to think the pain and fatigue are specifically related to the hypermobility.

Most ME simply does not fit an EDS cause because it comes on after infection or at leat appears out of the blue. EDS is there from birth.

 

What I am speculating is something along these lines:

(1) You catch a viral infection, and perhaps initially develop post-viral fatigue, which as we know often clears up on its own after 6 months or so, presumably as the virus is slowly cleared from the body tissues.

(2) But during this post-viral fatigue phase, in some people the MMP enzymes secreted by the immune system in the process of fighting the infection start to cause damage to the connective tissue, which leads to CCI/AAI, and then brainstem compression.

(3) Then once brainstem compression appears, it affects the autonomic nervous system, and turn causes immune abnormalities, so the immune system is no longer able to fully clear the infection, and/or the immune system starts behaving in a dysfunctional manner, leading to ME/CFS symptoms.

So in essence, the idea is that the viral infection creates the CCI/AAI, but once created, the CCI/AAI then acts to prevent clearance of the infection. So it is a vicious circle.

(4) Once you fix the CCI/AAI by surgery, normal autonomic nervous system functioning is restored (as indicated by the instant remission in POTS), which in turn restores normal immune functioning, which then after some weeks or months is able to clear the viral infections (or rectify any autoimmunity), leading to remission from ME/CFS.


Take all this with a pinch of salt, it's just a thought which occurred to me. I am just trying weave in a possible hypothesis to fit the facts that we know so far.


This autonomic-immune connection hypothesis was originally suggested by Jeff:

My thoughts are that the ligaments may only be eroded when there is a chronic low-level infection of tissues in close proximity to the ligaments. As mentioned, brain autopsies show enteroviral brainstem infection in ME/CFS.

And interestingly, one autopsy showed that enterovirus had infected the perivascular fibroblast cells in the brain; fibroblasts of course supply the raw materials needed to maintain connective tissue.

 

Note: I just edited my above post to include a point (4).

 

As of the moment I cannot think of a single viral infection that induces bone erosion. It is always bacteria.

And the point remains that bone erosion has never been found in PWME.

 

Oh yes: definitely. But it is equally true that her diagnosis of EDS was the result of her accidentally being sent to the wrong person to deal with her "ME" decline. Effectively she had been regarded as someone with ME who was also hypermobile (including easily dislocated joints). For the other two members, actual joint dislocations have not been a problem, but problems with walking, with neck support etc. have been pretty major. But then, their position is not as severe. I suppose that from my layman's point of view, the three of them suffered more skeletal and internal problems in proportion to the overall "severity" of their ME when compared to the rest of us.

It is also important to distinguish from hypermobility and EDS. I'm separating hEDS from EDS. The three members that I am talking about have EDS.

@Jonathan Edwards , I don't really see the relevance of your calculation to my example. I am not proposing that we just have a random number of people in my group with EDS, nor have I suggested that they suffer from hEDS. My suggestion is that ME is badly diagnosed, and that the proportion of people having undiagnosed EDS given that they have been diagnosed with ME may well be higher, reflecting the shoddy nature of much of the diagnoses of ME. There may be a factor with EDS that leads to an increased possibility of getting ME - but of course that is pure speculation. Or that some people with EDS in its early days are told that they have ME, which often then shuts down any more investigation. Two of them though did have sudden onset ME following infection, the other following giving birth.

What does intrigue me is that, for a long time, several of us have felt that those three members didn't quite fit the same ME pattern as the rest of us. Whether that was because they had EDS alone, or whether the ME lay alongside it, who knows? A key point will be to see how many symptoms remain after the surgery, but that will take time to evaluate, as there will be a long period of careful activity.

 

I thought it was ligament degradation that caused CCI/AAI, rather than it being a bone thing?


EDIT: Ah, I see from this article that there can be other causes for CCI/AAI:

 

it sounds plausible to me, that spine issues cause dysfunction autonomic (...++)
and that there may be a collagen problem, i can relate to

@Hip but why would this collagen/MMP/virus issue first of all affect the spine, in particular the upper part ?
not or so much less other parts of the body

and how could this happen in just a few years, as with the 3 patients so far (i understand they werent ill for long)

 

I imagine a virus might affect connective tissue in various parts of the body, depending on which organs get infected; but when it happens to affect the connective tissue in this critical part of the spine where it connects to the skull, perhaps that's when CCI/AAI arises.

I found it very interesting that within months of catching my own ME/CFS-triggering virus, I developed some connective tissue symptoms:

My gum line very rapidly receded in a matter of months; prior to the virus I had excellent oral health, but soon after catching my virus (which blood tests suggest is coxsackievirus B4, the same as Jen's), I was hit with sudden onset receding gums (periodontitis). Here is a picture of my receded gum line:

Rapid-onset receding gums caused by viral infection (connective tissue degradation)



Then at around the 12 month stage after first catching my virus, a new connective tissue symptom appeared: an unusual crêpe paper-like wrinkling of the skin throughout my body (but most prominent on the tops of my hands).


In fact it was these gum and skin tissues that around 12 years ago led me to looking into MMP enzymes, in an effort to understand what my virus was doing. And that's why, when I heard of Jeff and Jen's story, the first thing that came to mind were the MMPs. Though MMPs are not the only enzymes which break down connective tissue; there are also enzymes like neutrophil elastase and fibroblast elastase.