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

I think I have probably said enough on this topic. it has been helpful to go into more detail in discussion but I find that everything points to a small group of neurosurgeons operating without due indication based on speculative theories that do not make sense in terms of basic physiology. The Bragée clinic seems to have swallowed these stories.

 

Thanks @Hip I also think it's worth highlighting some of the differences between these theories.

I don't know where these figures are from but the consensus documents says that 135 or less is only potentially pathological. I suspect it's possible for people like gymnastics or ballet dancers to have a CXA lower than 135 but be perfectly healthy.

In this Swedish study the ME/CFS patients had a CXA of 148±10 degrees, which seems rather normal. That would be in contrast to the theory that a substantial subgroup of ME/CFS patients has very low CXA angles. So I'm not sure that the Swedish study should be seen as a confirmation of what Henderson, Bolognese en Gilete are saying.

I don't have much background in biology so forgive me if these questions are off. But wouldn't an issue of blood flow be visible for example on SPECT scan? I'm also thinking: if that blood flow problem was causing these severe ME/CFS symptoms for may years, wouldn't we expect that resulted in some permanent damage to neurons etc. Or wouldn't it in some patients become so severe that its cause becomes apparent? And if correct blood flow can be almost immediately be helped with traction wouldn't we expect more fluctuation of symptoms and disability than we normally see in ME/CFS patients?

 

I’ve been trying to say this but it’s often I think lost in all the discussion around my case, Jeff’s, Julie’s, etc. And that is that we are observing many different structural/mechanical neurological problems in patients, not just CCI/AAI. I have been arguing that what connects these observations are a) their association with connective tissue disorders and b) their association with abnormalities in spinal fluid and/or blood flow. The actual diagnoses vary—a lot.

The Swedish study does raise interesting questions re: the possible relationships between what clinicians have been observing in EDS patients and what we observe in ME/CFS patients. It does this both through the direct observation of hypermobility and hEDS in a large proportion of patients. It also does this by observing these intracranial hypertension signs, itself an overlap with what we see in hEDS.

What I find to be a big miss in this study is that it does not report the average measurements in patients w/ and w/o hEDS. As such, we don’t know how much of what they are finding is an hEDS effect or if it applies to the entire study cohort, including patients who do not have hypermobility. This is important to know not because hypermobility necessarily CAUSES or explains any of the things, but rather because we’ve seen these signs/morphological features reported in hEDS patients for some time, and it would be good to know if that is why we are seeing them in this patient cohort, too.

Also, note that Henderson and Bolognese, at least, are not and have never said anything about ME/CFS patients.

Some people may be able to live at < 135 degrees without ill effects, but note that it is not common to have a CXA that acute. I took all the studies on CXAs and pooled the results using simulation. < 3-4% of “healthy” controls have CXAs < 135 degrees.

I do think that the cranial settling/BDI concept is going to prove very important in all this. However, we are unlikely to have published data on this for some years.

Yes, and actually a SPECT scan is one of the scans Dan Peterson does on all of his patients. Mine showed hypoperfusion. However, I do not think SPECT scans are generally well-regarded in clinical practice.

Re: whether hypoperfusion causes damage, are you asking why haven’t we seen evidence of damage in ME/CFS brains if it is true that patients have chronic hypoperfusion? I do think we’ll start to find evidence of damage, or rather, I’ve hard about some early findings. However, damage (v. dysfunction) is hard to observe/describe given that we do not have any brains in our brain bank.

Here’s what we know about hypoperfusion so far. (There may be other studies, but this is what I have found.)

1. Natelson, Benjamin; Mao, Xiangling; Stegner, Aaron J; Lange, Gudrun; Vu, Diana; Blate, Michelle; Kang, Guoxin; Soto, Eli; Kapusuz, Tolga; Shungu, Dikoma C (2017), "Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity", Journal of the Neurological Sciences, 375: 411-416, doi:10.1016/j.jns.2017.02.046
2. ↑ Jump up to: 14.014.114.2 Costa, D. C.; Tannock, C.; Brostoff, J. (Nov 1995). "Brainstem perfusion is impaired in chronic fatigue syndrome". QJM: monthly journal of the Association of Physicians. 88 (11): 767–773. ISSN 1460-2725. PMID 8542261.
3. ↑ Jump up to: 15.015.115.2 Barnden, Leighton R.; Crouch, Benjamin; Kwiatek, Richard; Burnet, Richard; Mernone, Anacleto; Chryssidis, Steve; Scroop, Garry; Fante, Peter Del (2011). "A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis". NMR in Biomedicine. 24 (10): 1302–1312. doi:10.1002/nbm.1692. ISSN 1099-1492. PMC 4369126 . PMID 21560176.
4. Jump up ↑ Biswal, Bharat; Kunwar, Pratap; Natelson, Benjamin H. (Feb 15, 2011). "Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling". Journal of the Neurological Sciences. 301 (1): 9–11. doi:10.1016/j.jns.2010.11.018. ISSN 0022-510X.
5. ↑ Jump up to: 17.017.1 Yoshiuchi, Kazuhiro; Farkas, Jeffrey; Natelson, Benjamin H. (2006). "Patients with chronic fatigue syndrome have reduced absolute cortical blood flow". Clinical Physiology and Functional Imaging. 26 (2): 83–86. doi:10.1111/j.1475-097X.2006.00649.x. ISSN 1475-097X.
6. Jump up ↑ Freedman, M.; Kirsh, J. C.; Gray, B.; Chung, D. G.; Abbey, S. E.; Salit, I. E.; Ichise, M. (Oct 1992). "Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome". Nuclear medicine communications. 13 (10): 767–772. ISSN 0143-3636. PMID 1491843.
7. Jump up ↑ Chao, C. C.; Hu, S.; Pheley, A. M.; Schenck, C. H.; Grammith, F. C.; Sirr, S. A.; Peterson, P. K. (Mar 1, 1994). "Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients". Clinical and Diagnostic Laboratory Immunology. 1 (2): 222–226. ISSN 1071-412X. PMID 7496949.
8. Jump up ↑ Lange, Gudrun; Wang, Samuel; DeLuca, John; Natelson, Benjamin H. (Sep 28, 1998). "Neuroimaging in chronic fatigue syndrome". The American Journal of Medicine. 105 (3, Supplement 1): 50S–53S. doi:10.1016/S0002-9343(98)00175-2. ISSN 0002-9343.
9. Jump up ↑ CMRC Conference 2017 day 1- Prof Dr Frans Visser, retrieved Sep 3, 2019

This question is really interesting but I don’t fully understand it. Can you explain more?

 

Yes, that's right, as I understand it, pathological range craniocervical measurements alone are not sufficient for a CCI diagnosis.

Rather the diagnosis of CCI is made via a combination of factors, which includes the patient's craniocervical measurements like CXA, Grabb-Oakes and BAI, but also involves factors like whether or not the patient has the symptoms of CCI (the so-called cervical medullary syndrome symptoms, especially severe headaches and neck pain), and whether there is a reasonable explanation for the lax ligaments at the patient's craniocervical junction.

Dr Henderson in this 2012 video at 13:12 says that the above 3 (bolded) components are required for a diagnosis of CCI.

Dr Henderson in this 2019 paper on diagnosing CCI in the patient population with hereditary hypermobility connective tissue disorders says that CCI diagnosis also depends on whether the patient displays certain neurological deficits that are linked to CCI.


A list of reasonable explanations for the lax ligaments is the following:

Acute causes:
• Physical trauma (like a car accident or sporting injury)
Chronic causes:
• Developmental Chiari
• Occipitalization of atlas (congenital fusion of the atlas to the occipital bone of the skull)
• Klippel-Feil syndrome (congenital musculoskeletal condition involving fusion of at least two vertebrae)
Degenerative or inflammatory causes:
• Rheumatoid arthritis
• Lupus
• Neoplasm (an abnormal growth of tissue, such as cancer)
• Infections
• Surgery
Genetic hypermobility connective tissues disorder causes:
• Hypermobile EDS
• Marfan syndrome
• Stickler syndrome
• Down's syndrome


A list of neurological deficits associated with CCI found here (midway through document):

• Tender C1-C2
• Decreased gag reflex
• Hypoesthesia to pinprick
• Decreased vibratory sensation
• Hyperreflexia
• Dysdiadochokinesia

• Romberg
• Difficulty with heel to toe walking
• Abnormal gait
• Weakness
• Loss of abdominal reflex
• Babinski, Hoffman’s signs

That is how Dr Henderson diagnoses CCI, and Dr Gilete I believe follows similar criteria. Dr Bolognese's criteria also include examining the cervical medullary syndrome symptoms, but he additionally adds the further criterion that a patient must improve under invasive neck traction before he considers the possibility of fusion surgery. (Note that invasive neck traction is the gold standard; home over-the-door traction devices and physiotherapist applied traction are not as definitive as invasive neck traction).

Bolognese in this 2018 video at 1:12:44 says that some patients have pathological measurements indicating CCI, but show no symptoms. No surgery is advised for these patients.

I am not entirely sure about the differences between regular patients and EDS patients when it comes to the craniocervical measurements. Obviously EDS patients have a greater range of joint motion than normal people.

I read that about 1 in 15 people with EDS will go on to develop CCI due to a lack of connective tissue support at the craniocervical junction. Ref: 1

This post has been copied to the general thread about CCI. If you want to discuss it please do so there:
Concerns about craniocervical instability surgery in ME/CFS

 

The range of CXA in the healthy population is 160 to 145, and I believe I saw a paper stating that average CXA in healthy people was 158 (but I cannot find the paper at the moment). So an average of 148 is less than normal.

Don't forget that a pathological CXA is just one way that you can have CCI, but you have also have CCI if you have a pathological Grabb-Oakes, BAI or translational BAI. So not every case of CCI will involve a pathological CXA. So that effects the average CXA value.

In our survey of so far nearly 60 ME/CFS patients, of those positive for CCI, a pathological translational BAI is found in around 46%, a pathological CXA is found in around 38%, a pathological retroflexed odontoid is found in around 21%, a pathological Grabb-Oakes is found in 16%, a pathological odontoid over Chamberlain's line in 16%, and a pathological BAI is found in around 9%.

Most ME/CFS patients with CCI had more than one measurement in the pathological range.

One study found that hypoperfusion of the brainstem in ME/CFS patients was marked and constant.

I am guessing it is possible that the mechanical pressure on the brainstem resulting from CCI might lead to several things: blood flow reduction, but also CSF flow reduction, and perhaps neuronal dysfunction cause by the compression or stretching of the neurons and their axons.

 

If you read either of the full Henderson papers on cxa I believe he says that the mathematical modelling (finite element annalysis) shows that anything below 150 or 145 is abnormal and potentially pathological , but that below 135 is a different category, like clearly pathological.
In the study i think he said that he included someone with a 139 cxa bc of their clinical picture indicating greater disability.
The cxa does seem like its emphasized the most, but it seems that Bolognese and these other surgeons put a clear emphasis on looking at more than one measurement at once and also sometimes response to traction, and clinical picture.

In the Bolognese and Milhorat study that i posted in this thread and another thread, all of the supine measurements (cxa and others) were within normal range, and then when taken while upright, were quite different and clearly abnormal.

There were no healthy controls in this study (which is too bad) but there was a comparison between patients that had chiari plus connective tissue disorder, ans patients who had only a connective tissue disorder, and comparison between the measurements of cci on both of these populations.


The argument has been made that there are not studies validating these measurements as compared to controls, establishing a normal range, etc.

I can see this line of argument as valid but im not sure that we have enough information here to know how CCI used to be diagnosed and whether the measurements that used to be used (of which it seems the group that made the consensus statement has picked a few and simplified) had any more validation than cxa, Bai, etc.
In fact, it seems like perhaps, CCI has just not been an object of much research and interest and clinical practice until recently. So perhaps there just isnt a ton of data.
@Jonathan Edwards says, you dont need these measurements (which he points out do not have controlled studies , besides the mathematical modelling) to diagnose CCI, the compression is obvious on scans and clinical picture.

But is there any citations or body of evidence to show that the "old way" of diagnosing CCI is correct?

I would think that Bolognese or Henderson would have similar confidence in their own clinical judgment. But I think the history of these measurements and what the "normal range" is need to be clarified and we cant just rely on someone's clinical experience.

My perspective, which may be somewhere in the middle on this, is that I have confidence in bologneses acumen as a surgeon and innovation in surgical techniques, and confidence in his diagnostic abilities. But i do wish that some of these measurements were validated against healthy controls, which seems like it would be easy to do.

I dont think , personally, that dr b or Henderson have refused to do those kind of studies because they dont believe in science, I just think that it seems like neurosurgeons may see themselves more as artisans than scientists and be less interested in proving their findings than getting results clinically though.
So like i said i dont think theres any sinister reason for skipping the step of validating these measurements against controls. And im not sure if the "old way" of diagnosing based on eyeballing scans and more obvious clinical signs is any more validated than the methods we are discussing. But i do wish there were more studies on all of this.

Also, i still dont understand what a finite element analysis is. Anyone know?

 

The improvements that people have after manual traction are not anywhere close to full recovery. It seems to take more force, as in invasive cervical traction, to relieve me/cfs and pots symptoms very significantly.

 

So, in the citations for this study, i found a Milhorat study that does indeed include healthy controls , as well as controls that have CM I, when comparing these measurements. Its unfortunately paywalled.

Can anyone find the full text
https://thejns.org/spine/view/journals/j-neurosurg-spine/7/6/article-p601.xml

I very much like this line of argument and id love to see more study on this. Especially with the recent, highly circulated article on the brain "washing" itself during sleep via csf flow. Saying more would get into entirely speculative realms...

 

Of course, trial variables can be manipulated in such a fashion as to still enable biases to tip the scales.

A general rule of thumb, but precisely the rub in some medical communities,i.e. clinicians with apparently good reason can, in some instances, doubt the voracity (integrity?) of the trial results.

 

As you indicate there are some studies that reported hypoperfusion in ME/CFS, but if this was what's causing the enormous disability associated with this illness and hypoperfusion is something that we can actually measure, I would assume that the results stand out more starkly than they did in the studies we have.

This is actually a more general point. ME/CFS causes enormous disability in most patients. It can do that for years without showing much abnormal on standard medical tests. We even have very severe patients, who look as ill as human beings can be, yet their medical tests seem relatively normal.

So I would assume that indicates that whatever is causing the illness is something that we can't see or measure very well with the tools and tests that we currently have. So a theory that proposes that the disability in many ME/CFS patients is caused by a problem that would be visible on these medical tests (like a SPECT for hypoperfusion or an MRI for structural damage) seems rather improbable to me.

Don't know if it's a good question really, but I was wondering: if posture makes a big difference and traction can cause spectacular symptom relief wouldn't we see more variability in ME/CFS? Like patients getting worse or better depending on whether they lie down more or sit with a different posture etc. Or isn't that how it works? I remember that you said some symptoms worsened depending on how you hold your head etc.

I don't think that website is a reliable source. I contacted them because I thought some info they provided was inaccurate. From their response, it seems that they thought CCI was a condition almost exclusively associated EDS. I wrote about this on the other thread.

Range normally means from minimum to maximum, so that doesn't seem right. Jennifer used the studies that reported a CXA in a healthy population, simulated them and came up with an estimate of 3-4% of healthy controls that have a CXA lower than 135. What you report seems more like a range of 1 standard deviation from the mean taken from one of these studies.

The mean CXA reported by this Swedish study seems a bit low but it's almost identical to what Bothelo & Fereira reported in healthy controls (148°± 9.8°) and within one standard deviation of all the other estimates in healthy controls Jennifer summarized on MEpedia. So I think it's correct to say that it looks rather normal.

I suspect the reference values refer to supine measurement, no? If upright measurements show more abnormal values, that would also be a bit worrisome because if people are misinterpreting these, it might result in overdiagnosis of CCI.

Yes, this is what worries us.

 

How many SPECT scans were done? My dear friend who passed away showed hypoperfusion on one scan, and a few years later the hypoperfusion disappeared. I don't think it's a good indication on the severity of disability because he was feeling much worse on the second SPECT where there was no hypoperfusion.

 

Of the 53 ME/CFS patients positive for CCI in our survey, 36% experience either transient paralysis (eg, breathing muscles fail) in certain head/neck positions, or a worsening of symptoms in certain head/neck positions. So there is head/neck position sensitivity in some ME/CFS CCI patients.

Interestingly enough, more than half the patients with such head/neck position sensitivity had retroflexed odontoid (a type of CCI in which the odontoid its tilted so that it pokes into the brainstem).

It's just me who put the numbers 160 to 145 in that order. I think you would prefer it written 145 to 160. The full range for CXA is this:

Normal CXA = 160º to 145º, borderline = 144º to 136º, pathological = 135º or less.

Sources: Bolognese 2015 video at 14:28. Also Henderson 2016, Henderson 2018, Henderson 2018 video at 8:17.

Interesting. I am not quite sure why that mean clivus-canal angle figure of 148º for healthy controls differs from the mean CXA figure of 158º for healthy controls I mentioned earlier, which I have just found the reference for: this paper says:

Maybe different populations might explain it. Your Bothelo & Fereira study finding 148º was conducted in Brazil, whereas Nagashima and Kubota was conducted in Japan.

Another factor might be a possible a difference between the clivus-canal angle of Bothelo & Fereira versus the clivo-axial angle of Nagashima and Kubota.

According to this paper, there are different ways to measure this angle:

Though as far as I can see, the clivus-canal angle looks the same as the clivo-axial angle.

 

Now published, thanks to @Grigor for noticing it.

https://www.frontiersin.org/articles/10.3389/fneur.2020.00828/full

 

Merged thread

Neck injuries,hypermobility and signs of Intracranial Hypertension are common among patients with ME/CFS

We present new findings supporting this headline today in the highranked Frontiers of Neurology. It can be read or downloaded with open access: https://www.frontiersin.org/articles/10.3389/fneur.2020.00828/full

We chosed this journal as we think it is important to stress the neurological character of ME/CFS. It is estimated that more than 40 000 people in Sweden are suffering from ME/CFS, a number that may rise substantially in the future. Viral epidemics are well-known triggers for the onset of ME/CFS and the current COVID situation will most likely make the disease even more common. There are only two ME-dedicated clinics helping these patients in our country, both in Stockholm.

Our article might be contribute to a potential explanation behind the disease in at least a subgroup of patients. Clinical data from the Bragee ME-center indicated that hypermobility and strictures in the cervical spine were common in patients, of which the latter could be a sign of previous neck injury. To study this further, physicians at the clinic recruited 229 patients who were newly diagnosed with ME/CFS and consecutively invited to participate. The results were striking. Every second patient were hypermobile, and radiological examinations (MR) revealed that 80% had obstructions in the cervical spine and 83% displayed signs of elevated intracranial pressure. These numbers are far higher than what could be expected in the normal population and indicate that such abnormalities may be important in disease genesis, at least in some cases of ME/CFS.

These findings might explain many of the symptoms present in ME/CFS. It is today rather clear that ME/CFS is a neurological disease, and interestingly, nearly all patients in the study experienced hyperalgesia and 3 out of 4 fulfilled the criteria for Fibromyalgia. We have a new project approved in which we seek to confirm these findings, by determining intracranial pressure more directly.

Several projects are running attempting to verify these findings and evaluate treatment options, says Bo C Bertilson, MD and Research leader, affiliated to the Department of Neurobiology, Care Sciences and Society, Karolinska Institute.Today’s research within the field are focused on neuroinflammation, which likely is of importance, but our data may very well complement and add to the field of neuroinflammation. There is an obvious need for clinical research in ME/CFS and patients and relatives at the Bragee ME-center contribute immensely to this.

Please welcome to read, comment on and maybe spread the article.

 

I’m confused Is this the same paper that’s been discussed earlier in this thread? That was published in 2019?

 

It first appeared as a pre-print in 2019 and has now been properly published in 2020.