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

So if the CSF is not going where it is supposed to go, but is still flowing unhindered, that presumably means it is going somewhere else, somewhere it is not supposed to go. Is it known where it does flow to in these circumstances?

 

The CSF around the spinal cord is just a dead end reservoir. I am not sure that we understand all that much about what the CSF is for but one likely thing is that it provides a fluid cushion for nerves to move in. There is no particular need for it to be produced or absorbed that I can see. I don't know why we have ventricles inside the brain with fluid gradually flowing out of them.

Quite a few body spaces have fluids. The pericardium contains fluid that is not produced or absorbed anywhere in particular. Since the surrounding tissues are sopping wet as well a lot of fluid movement is just diffusing to fill gaps I suspect.

 

Maybe they believe the hypothetically sensitised pain might explain the fatigue, PEM, OI and other symptoms?

 

No, I don't think it flows anywhere else. The failure of resorption means that the production rate has to reduce, but the pressure in the system goes up.

 

I mean, we do have reason to think CTD cases are relevant to this study at least, as they identified hEDS in 20% of cases.

That is actually one thing I find confusing about the study, that we get no sense of the correlation between hEDS and the other findings.

Again, I don’t know if it is true (re: the reason for the absence of papilledema in pwEDS with IIH)...it’s just been offered of an explanation for a normal eye exam. In my case, I did have excess cerebrospinal fluid in my optic nerve sheath observed my MRI. I do not know if papilledema would have been observed by an ophthalmologist.

I do think our understanding of IIH is changing somewhat, though. Your discussion focuses on failure to reabsorb CSF. However, many cases actually seem to be related to venous outflow. Or at least, there is growing evidence IIH can be successfully treated in many cases by stenting the transverse sinuses. I don’t think anyone fully understands why, or whether the stenosis is cause or consequence.

In my case, I did have intracranial hypertension pre-surgery due to CCI and “functional cranial settling.” This was quite apparent through the dramatic changes in my ICP readings when in traction, neutral, or when you pushed down on my head. I cannot explain this. It was nonetheless true. It was in my case, though, seemingly related more to blood flow than to CSF flow.

I find this a little confusing only inasmuch as some people do seem to think that it matters (the flow of CSF between the brain and the spine). https://n.neurology.org/content/45/9/1746.short And isn’t this part of how Chiari is thought to cause or be related to syringomyelia?

There also seems to be an association between “Chiari” and IIH but this paper seems to suggest the relationship could go in the opposite direction: http://www.ajnr.org/content/33/10/1901.short

I can appreciate that the anatomy doesn’t make sense. But I actually think there’s a lot we still don’t understand about the anatomy, especially dynamically.

 

I love how polite the study authors were. “You told these people their symptoms had psychosomatic explanations but maybe their brains slipping out of their heads when they stand have something to do with it.”

 

I found a diagram of CSF flow in Wikipedia:

Flow of Cerebrospinal Fluid in the Brain and Spine
​

The Swedish study by Bragée et al seems to be a bit of departure from the theories that Dr Fraser Henderson talks about. Whereas Dr Henderson focuses on strain-induced neuronal damage as the basis of the symptoms caused CCI and related conditions (in this video at 10:42 he talks about the neurobiology of stretch injury), by contrast, the Swedish study seems to focus on cerebrospinal fluid blockage being the central mechanism.

However, neither case would seem to explain how those with CCI instantly improve under neck traction. If we assume that Dr Paulo Bolognese is onto something with his neck traction tests as a means of diagnosing CCI, then we need to explain why many symptoms of CCI can be immediately ameliorated by traction.

But as far as I can see, neither the neural strain theory or the CSF block theory would explain this instant improvement in symptoms from traction.

The neural strain theory detailed by Dr Henderson proposes that neurons and their axons are damaged and destroyed by strain. Well, that would not explain the traction results, as it would take some time for neurons and axons to regrow once the strain is released, assuming they are able to regenerate.

But I cannot see how CSF flow blockages would explain the instant traction results either, as even if traction unblocks the CSF flow, I cannot imagine that that would result in instant amelioration of symptoms. If there is a CFS blockage, that perhaps might allow metabolic by-products to build-up in the brain, or cause a depletion in the number of immune cells available in the brain, which could I guess lead to symptoms. But on release of the blockage via traction, I would think it would take some time before those issues were rectified.

So what might be the mechanism behind CCI symptoms? Perhaps a blockage of blood flow to the brainstem could explain it. The mechanical pressure placed on the brainstem will block blood flow, and then once the pressure is alleviated by traction, blood flow resumes, and normal nerve function is restored. Or perhaps mechanical pressure on the neurons and axons in the brainstem directly impedes their functioning?

It's a common experience to have an arm go numb due to sleeping on it. Presumably that arises from cutting off the blood supply to the nerves in the arm, or from direct pressure on the nerve resulting in temporary nerve dysfunction. But as soon as you remove the pressure, the numbness dissipates within minutes.

 

'hEDS' is not CTD. Even the 2017 criteria are likely mostly to pick up polygenic hypermobility and that is not CTD. We have a serious problem with degraded information here.

Yes but you cannot blame lack of optic nerve oedema for not finding papilloedema if your evidence for raised pressure (as here) is optic nerve oedema. It's a plain backwards argument.

Which would work by inhibiting reabsorption of CSF. Are you familiar with Starling forces, Jen?

Yes, that is what I said, unless we are considering Syringomyelia, which is an aberrant situation where CSF gets forced into the centre of the cord. I don't know of anyone who thinks it matters beyond that, except perhaps these Swedes who do not seem to have a basic grasp of physiology. I admit that is not saying a lot because virtually all of my rheumatological colleagues had no basic grasp of physiology. I think it is important to realise just how much clinicians bullshit about this sort of thing.

There is a lot we do not know but there are certain basic things I learnt 50 years ago that remain valid because they are just simple shapes and pressures. Theories that disregard such fundamental things don't have much change of being right.

 

I have seen that sort of misinterpretation so often I think it is highly likely, especially when the majority of the radiological and neurosurgical world do not seem to buy in to this at all.

I have no idea but from what I have seen of the stuff on measurements so far maybe because they think they can tell what matters but actually have no idea. Again, that is something I have seen many times.

To be fair, you are right. Understanding fluid compartments is complex. But the main problem is that people think they can learn about it from books and equations, without having a practical non-verbal model in their head of what is actually going on.

When I started out in synovial physiology in 1980 the received wisdom was that the fluid was secreted as an ultra filtrate from synovial venules and absorbed by the lymphatics. Sounds OK until you point out that the lymphatics are in the synovium as well - in the same place as the venues. So the fluid is secreted and absorbed in the same place. How does that make sense? It turns out that there is a beautifully cunning process that has nothing much to do with bulk fluid flow but ensures that the volume in the synovial cavity (not the synovium) is constant. Something pretty similar is likely to apply to CSF. But the Swedish hypothesis does not even work if you forget the niceties.

 

The NIH website classifies hypermobile Ehlers-Danlos syndrome as an inherited connective tissue disorder.

 

I am sure it does.
Doctors often get things wrong, or muddled, or fudged, and medical websites even more so.
I am sure there are a small number of people with monogenic dominant CTD of the EDS type presenting mostly as hypermobility but 'hEDS' as defined now, and even more so in 2007 captures a completely different population. This is not just my opinion. It is the opinion of all the rheumatologists I have recently contacted about it.

 

My money is on sudden restoration of normal blood flow.

I base that on nothing but my own subjective experience, and knowing what the metabolic & neurological consequences of hypoperfusion are. Hypoperfusion is something I think we can pretty confidently say *is* happening in ME patients. Moreover, blood flow is the only thing that would change that quickly.

There is still a neuro piece that is pretty immediate. A lot of the damage under "neural strain" isn't really overt damage requiring regrowth. It's more, subtle stress that alters the function of the nerve and can change the shape of neural membranes. A lot of people report under traction that they can lift their arms again, that their muscles weakness improves, and we've seen several people who have improvement in their neurological exams while under traction. So there is an immediate neurological effect, but that seems to be referable more to specific nerves in the cervical spine. It doesn't explain the whole brain effect.

The question, then, is what is causing the poor blood flow in the first place?

 

And not just normal fluid dynamics, but what happens in various pathological states. I tried reading about what happens after TBI, for example, because a lot of researchers have noted the similarities between some aspects of TBI and some aspects of ME, but I gave up. Everything is conditional because it's a dynamic system, constantly adapting to what is happening in the moment.

This conversation is helpful because it's raised for me a lot of questions I haven't asked. I don't know why I had an empty sella and excess spinal fluid in my optic nerve sheath or transverse venous sinus stenosis (all strong signs of IIH), but I did. And yet, when I had a high volume lumbar puncture, while some specific symptoms improved *a lot*, my vascular neurosurgeon said, "Yeah, spinal fluid isn't really your problem." I suppose if it had been, if I had looked like the patients who he ends up shunting, I would have had a much more dramatic symptom response. However, I did have diverticuli in my lumbar spine and when I had a blood patch for them, I was able to be upright longer without feeling ill. Yet, when you put a bolt in my head, I have high pressure, which would improve with traction and worsen with whatever the inverse of traction is. But I wouldn't have it all the time––it would fluctuate with blood flow and with my own breathing. And yet, when I woke up after surgery, the pressure in my head and behind my eyes I'd had every day for eight years was completely gone. Except it came back four times this fall, each time after self-healing from a spinal fluid leak, sometimes in my skull, sometimes between my shoulder blades.

These are all true things that happened and there is a reason for them, but it's really, really complicated.

Fluid, man.

But I see all that and my gut says: connective tissue, man.

My MCAS was and continues to be a major trickster/wild card/"fun" factor interacting with all of this.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681798/

So I found this paper , which explores the connection between ccj problems and intracranial hypertension. It's interesting and detailed . It seems @JenB is right that the connection may be mediated more via venous issues/hemodynamic problems caused by neural compression rather than direct blockage of csf flow.

 

Haha. If only it was fun!

 

It seems like in TBI, much of the damage occurs because of processes initiated aftee the initial damage, like oxidative stress, excess glutamate, glial activation , and so id wonder if a TBI plus some kind of toxic exposure or pathogen would produce something similar to ME. I have read that TBIs are underdiagnosed in the military, ans we all know that gulf war veterans were exposed to a plethora of toxins, from cyanotoxins to sarin gas, and many other awful things. So I wonder if having structural damage could make one more vulnerable to other forms of cell danger response or inflammation or cellular stress... This might explain variability in correlation btwn measurements and pathology

 

This is a really interesting paper. Thank you.

This outlines a lot of what we have been discussing here:

“malformations of the base of the skull and Chiari malformations that can block CSF flow resulting in hydrocephalus [61–65]. Connective tissue disorders, such as rheumatoid arthritis and Ehlers-Danlos syndrome, can cause tears, degeneration, ligament laxity, and cranial settling. Cranial settling causes the skull to rock back on the CCJ and sink onto the upper cervical spine during upright posture [66, 67]. In contrast to the brainstem getting pushed down into the foramen magnum as occurs in Chiari malformation, cranial settling shifts the position of the CCJ upward relative to the brainstem. The outcome is similar to basilar invagination and can cause hydrocephalus.”

I didn’t say it, though! Michael Flanagan, whoever he is, did...

 

This paper seems to contain a fair amount of new knowledge and speculation but is a great review with lots of references...I will be digesting this for some time. What a great find @debored13

“Researchers have also argued and shown that a significant amount of CSF flows into the capillary veins to exit the subarachnoid space. In either case, the absorption of CSF by the arachnoid granulations or by the capillary veins is affected by downstream venous pressure and flow. An increase in venous pressure in the superior sagittal sinus decreases the CSF pressure gradient, which decreases flow and increases CSF volume in the brain. Conversely, venous drainage is affected by the free flow of CSF. An increase in CSF volume in the brain can compress veins and decrease drainage.:

This is basically talking about the relationship between CSF and venous outflow that I alluded to in talking about my own case. Here they seem to be suggesting that the relationship between excess CSF in the brain and impaired venous outflow is bidirectional.

“Compression of the veins and decreased venous outflow also decreases cerebral perfusion pressure and blood flow in the brain [71, 186, 229]”

I would be curious to know in the Swedish study cohort, how many people have transverse venous sinus stenosis (TSS), which is found something like 80% of people with IIH. I had this. Of course, that would require an MRV, which would be a tall order. Higgins I imagine has some, clinically. I hope he does a larger case series...

 

Michael Flanagan is speaking your love language @Hip!

“Because of this, the author has also long maintained that the perivascular spaces serve as the lymphatic system of the brain and that sluggish CSF flow may play a role in pathology of neurodegenerative diseases and the increase in the presence of breakdown byproducts, viruses, bacteria, and heavy metals such as aluminum and iron [20, 21, 28, 91, 98, 102, 128, 234]. More recently it was discovered that in addition to providing pathways for the removal of wastes, the glial support cells that form the perivascular spaces also act as macrophages, which led to the term glymphatic system.”

 

That looks like a speculative review in a throwaway journal.
The abstract is typical of the sort of word salad you get with reviews these days.

The problem we have is that the medical profession now works in an environment where it can tell as many fairytales as it likes and someone will publish and patients will come and think they are being told facts.