Signs of Intracranial Hypertension, Hypermobility and Craniocervical Obstructions in patients with ME/CFS (Pre-print 2019/published 2020) Bragée et al

Signs of Intracranial Hypertension, Hypermobility and Craniocervical Obstructions in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Björn Bragée, Anastasios Michos, Brandon Drum, Mikael Fahlgren, Robert Szulkin, Bo C Bertilson.

Preprint:
https://osf.io/qwn5h/

 

Wow, those percentages seem really high. It's a shame there's no control group though. Hopefully this will be followed up.

 

Before we get flooded with cries of "see, see, definitive proof at last!!", I just want to highlight that, at least in my view, this is just the very start of the process that needs to be gone through to establish the prevalence of 'neck/spine issues' in our patient population, and then to establish the value, or otherwise, of surgery.

 

Here's a thread about another study by some of the same people:

Craniocervical dysfunction, neuroinflammation and infection in ME/CFS ws healthy controls (planned study) Bragée Clinic, Sweden

https://www.s4me.info/threads/craniocervical-dysfunction-neuroinflammation-and-infection-in-me-cfs-ws-healthy-controls-planned-study-bragée-clinic-sweden.12289/

 

I am not sure it is even a start. As @borko2100 points out there are no controls, the study is unblinded and based on a tertiary clientele.
Most strikingly it looks as if most PWME have not one but four causes for their illness. None of which would fit with the known epidemiology in terms of following viral infections and having two age peaks, neither of which relates to the age when people get cervical stenosis.

 

But what's the point in being right if you don't get say "you see, I told you so"! It takes all the fun away if you cannot say that!

One of the ideas some of us had when first contemplating craniocervical instability, Chiari and spinal stenosis in ME/CFS was that it could be the blockage of cerebrospinal fluid (CSF) flow which was causing issues.

CSF flow blockage often leads to intracranial hypertension (raised CSF pressure), so the fact that this Swedish study found potential CSF blockages (in the form of cerebellar tonsil decent and spinal canal obstructions) as well as intracranial hypertension suggests that CFS flow stagnation might be common in ME/CFS.

My thoughts were that since much of the brain's immune system resides in the cerebrospinal fluid, if the CSF flow is stagnated due to mechanical obstruction, then presumably the immune system is going to have a hard time coping with any viral infection that enters the brain.

Thus having any form of CSF obstruction — whether CCI, Chiari, cervical spinal stenosis, etc — may be like a time bomb in the body: it may not cause many symptoms on its own, but if you are unfortunate enough to catch a virus that manages to breach into the brain, then the compromised CSF immune system may have a hard time clearing this virus from the brain.

Perhaps the infected brain may then have to fall back on its resident microglia to fight the infection — and these microglia once activated may create some of the symptoms and problems of ME/CFS.

Anyway, that's one hypothesis of how viral infection plus a CSF obstruction may lead to ME/CFS. It ties together the viral theories of ME/CFS with these newly-discovered structural abnormalities in ME/CFS.



Some info about the CSF-based immune system in this article:

 

I have trouble buying intracranial hypertension plays a major role in me/cfs for a couple reasons. There is not the progressive visual loss and eventual blindness in me/cfs. Nor do we see that the most severely ill more likely to develop visual loss and blindness. Even if intracranial hypertension underlied a subgroup of me/cfs it would already be more common than iih (1/100k). So, you would expect it to be picked up on.

 

Blindness is not an inevitable part of intracranial hypertension.

“approximately 1-2% of new cases of IIH are likely to become blind in a given year.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722545/

However, I have seen discussion that papilledema may be less common in people with hypermobility who have IIH because the optic nerve sheath essentially self -fenestrates (about fenestration: https://emedicine.medscape.com/article/1891241-overview). This is due to the elasticity of the optic nerve sheath. I am trying to find a reference for this. It may just be a theory.

The absence of papilledema has been noted by both Liu and Higgins. (references here: https://www.me-pedia.org/wiki/Intracranial_hypertension)

If true, that could explain why IIH is so often missed (in addition to which, we have so many symptoms besides IIH symptoms). Interestingly, my elevated intracranial pressure was only accurately measured via ICP bolt. My opening pressure on lumbar puncture was only “high normal.” I had excess fluid in my optic nerve sheath and probably would have been categorized in this study as a person with a higher than normal optic nerve diameter, yet I had no vision problems whatsoever (until my case got much worse post-thyroidectomy, when I would occasionally have blurry vision or weird spots).

I think there may be complex ways in which the connective disorder piece and co-morbidities complicate the clinical presentation and classic signs/measurements, making all this harder to recognize.

Also, in CTD land, it is quite common to cycle between high and low pressure, several patients and multiple doctors have told me. Since surgery, I have had recurrent spinal fluid leaks that I don’t think I would have noticed when I had ME (too many symptoms!) as well as rebound high pressure. So at least for those with CTDs, it is possible the fluctuation of pressure may reduce the likelihood of developing the long-run optic nerve damage you might find, say, in an obese patient without a CTD.

 

What´s CTD?

 

Connective tissue disorder? Connective tissue disease?

 

I think this is highly unlikely.

It is well known that papilloedema is slightly less frequently observed in the elderly, but I cannot find any evidence of this most common - almost cardinal - sign of intracranial hypertension being less frequently observed in patients with CTDs. In any event, hypermobility is not a CTD.

Many of the other symptoms of intracranial hypertension - extremely severe headaches, vomiting, pain on eye movements, diplopia - are not consistent with the presentation of ME. Intracranial hypertension patients also often report that symptoms are worse in the mornings (due to plateau waves occurring more commonly during sleep); this, again, is not consistent with ME. Intracranial hypertension is very strongly correlated with obesity; ME is not. ME patients do not typically exhibit abnormalities on visual field testing so far as we know. CSF analyses have been performed on ME patients in the past; consistent abnormalities in opening pressures on lumbar puncture would have been documented.

Finally, there would be evidence of cases of ME - even in a small subset - worsening to the point where irreversible cerebral ischaemia had occurred.

 

Iirc Paul Cheney said he found very high pressure on spinal tap in incline village patients. Idk if he published these findings though.

 

Hes still alive. Does anyone know how to contact him?

Also, re: this study. I am in favor of studying this. I have methodological concerns. Like with the upright MRI, it can be hard to get a clear picture if patients are very symptomatic. So ironically you may either get not clear pictures, or have a less severe patient cohort that you're studying, if you are having people fly out and do it in one day, without medication.
So while its good that they are studying this, I think it's an ex of how researchers should listen to patient input about study design.

 

Have you read the references on the MEpedia page? The people working on this in EDS and ME/CFS have discussed some of the issues you have raised.

 

I read on another forum that Dr Cheney stopped emailing with patients back in 2016.

 

I will try to summarise a few points on anatomy and physiology, as I understand them.

1. CSF is produced by choroid plexus within fluid spaces called ventricles deep inside the brain and flows out of the brain at the fourth ventricle into the subdural space between the brain and skull. The CSF around the spinal cord is a dead end and not involved in any directional flow.

2. Therefore, cervical spine stenosis has no effect on CSF flow in the skull so does not affect intracranial pressure. It is irrelevant to any theory of raised intracranial pressure.

3. The same almost certainly applies to craniocervical instability since it does not interfere with circulation of CSF. Unless there is associated Chiari Malformation, in which case it is the Chiari that is the problem.

4. Chiari Malformation, if major, can lead to compression of the cerebellum on to the brainstem, which can block the outflow of CSF from the inner ventricles to the brain/skull space. This can lead to raised pressure within the brain but should not raise the pressure of CSF outside the brain. Such an effect is visible on an ordinary CT or MRI scan as an increase in size of ventricles relative to the brain/skull subdural CSF space. As far as I am aware nobody has said anything about such an appearance in any cases of ME/CFS.

5. Chiari Malformation comes in all degrees and over diagnosis of mild 'Chiari' is something that has been a concern for decades.

6. As far as I can establish the consensus view is that Chiari is not associated with EDS. The suggestion of an association comes from the Bolognese group in 2007. However, at that time the EDS criteria were even vaguer than they ae since 2017. Moreover, the report is based on a cohort of 'Chiari' cases attending a tertiary referral centre. It may be of note that they found that the combination of 'EDS' and Chiari was eight times more common in women. As far as I know EDS is not more common in women but 'hypermobility' as judged by Beighton score is much commoner in women because it does not have a different scale by gender and women have more mobile joints (elbows in particular). Everything points to the 'EDS' cases in this study being polygenic hypermobility and since the rate was only about 10%, which is normal, I doubt anything was found more than expected by chance. Which suggests that the consensus view is correct - there is no association with EDS.

7. The population based studies I have seen do not indicate any association between EDS and ME/CFS.

8. Idiopathic intracranial hypertension (IIH) is essentially unrelated to any of the above because the problem is failure to resorb CSF in the subdural brain/skull space. There is no blockage to flow. I do not know the detail of the imaging but I would not expect increase in ventricle size relative to subdural space. That may be why optic nerve oedema has been used to judge raised pressure in these cases.

9. Optic nerve oedema can occur with both an obstructive cause of high pressure and IIH. Note, however, that we cannot say that raised pressure may have been missed in CTD cases because the optic nerve is protected from oedema if the only evidence of raised pressure is optic nerve oedema. (And we have no reason to think CTD cases are relevant to ME.)

These are some of the reasons why I have said the anatomy and physiology do not add up.

One particular issue that worries me is that this group has chosen to send patients to a clinic in London that is highly controversial in terms of its interpretation of findings. There are fully competent neuroradiologists in Sweden, I am quite sure.

 

In the study plan document, they outline the only reason sending patients to London is due to lack of upright machine in Sweden (or anywhere closer for that matter). The London part is an extended study where only 10% of patients are included and according to the same document it would be performed in Stockholm if such a machine became available in time. Actually I think they can perform most of these measurements regardless in Sweden in the non-upright MRI. Anyway, I'd be curious to know why the London clinic is considered controversial.

Regarding the study itself, the observations are the more curious part to me. Actually the hypothesis outlined in the abstract is nothing more than figuring out whether hypermobility or craniocervical obstructions are overrepresented in ME/CFS. If the measurements were done correctly by a competent radiologist, it seems to confirm their hypothesis. 80% with obstruction in cervical spine sounds really high. 50% (h)EDS sounds really high as well. But obviously it leads to the question whether these findings indicate correlation or causation in terms of ME/CFS.

 

@Jonathan Edwards you have explained that CSF is produced in the brain and then reabsorbed in the subdural brain skull space. But How does the CSF then reach the spinal column (for example when taking a lumbar puncture in, it is taken from the spine) and howdoes CSF move around the spine? Is the CSF then absorbed into blood?

 

It is as bit more than that:To test the hypothesis that hypermobility and craniocervical obstructions is overrepresented in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and that a large portion of these patients may have a degree of intracranial hypertension explaining many of the symptoms of the ME/CFS syndrome.

I think that is intended to be read as implying that they think that hypermobility and craniocervical obstruction are potential causes of intracranial hypertension - which might explain symptoms. But, as indicated, I t don't think we have any reason to think these are potential causes of cranial hypertension in this context. If Chiari was involved it would have to be quite major and there would need to be an explanation for the absence of expanded ventricles.

The key problem for me is the assumption that somehow they are studying evidence for a relation between cranial hypertension and ME when they aren't.

The reason I say the London clinic is controversial is that I have seen a document produced by radiologists and neurosurgeons, and I am afraid I forget where from, which indicates that in the UK at least upright MRI is not thought to provide useful information. I personally cannot see why it should since we are not talking about upward migration of the dens of the axis in these cases. (If there was upward migration one could see it on an ordinary lateral cervical spine x-ray.)