Have you ruled out Chiari or Craniocervical Instability (CCI) as a cause of your CFS

Daffodil

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i actually am not sure it was mattie i was talking about. that is why i did not mention any names.

@mattie i am sorry for asking this again because i am sure i have asked this before...but how long were you sick before surgery and what is your age? i am just too foggy to search the thread.

i ask because i am 48 and have been sick almost 27 yrs. i am 110% sure that if i were to get a perfect surgery for CCI / AAI, i would still be pretty ill for a long time. I would imagine it would take so long for my system to recalibrate itself after decades, and, with aging on top on if, i am pretty sure i would never get back to even close to normal. there has to be a lot of cellular damage from that kind of inflammation

personally, i am just hoping to be able to think clearly. that is really all i want out of life now. ugh that is sad lol
 

pattismith

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We have no idea what the “death rate” is for ME patients. A meta-study of 2274 procedures (for people with a wide range of conditions) found it to be 0-0.6%. Here is the research on complication rates: https://www.me-pedia.org/wiki/Craniocervical_instability#Surgery
This page is a great contribution, thank you Jen!!

But Pr J Edwards clearly wrote that among the rheumatoid patients that undertook CCI surgery in his practice, the mortality rate was about 50%....And that the other 50% either got complications, either got worse!

So maybe the good studies published (with zero death and good outcomes) does not reflect what happens in most other practices that don't publish their success rates...
 

JenB

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This page is a great contribution, thank you Jen!!

But Pr J Edwards clearly wrote that among the rheumatoid patients that undertook CCI surgery in his practice, the mortality rate was about 50%....And that the other 50% either got complications, either got worse!

So maybe the good studies published (with zero death and good outcomes) does not reflect what happens in most other practices that don't publish their success rates...
Prof. Edwards is speaking from his personal experience, not the systematic evidence. Maybe there is something specific going on in the cases he was referring for surgery that made them unusually dangerous or high risk.

Here is the meta-study of 22 different studies: https://academic.oup.com/neurosurgery/article-abstract/67/5/1396/2563905

I highly doubt that his personal experience is the norm and that these 22 studies represent some extreme bias that suppress the mortality rate from 50% to essentially zero. It’s certainly possible but less likely than the alternative.
 

jeff_w

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Hi Everyone!

For the past year and a half, I have publicly proposed that ME/CFS could have a mechanical basis. Specifically, I’ve proposed that brainstem compression from craniocervical instability (CCI), atlantoaxial instability (AAI), as well as spinal cord compression (cervical stenosis) or stretching (tethered cord) could potentially be the ultimate cause of ME/CFS for a significant subset of people – or possibly for the majority of them.

People in the ME/CFS community often ask me how a mechanical problem, such as CCI/AAI or cervical stenosis, could possibly relate to the metabolic trap hypothesis proposed by Dr. Davis and Dr. Phair. Some people with ME/CFS have said,

“If the mechanical paradigm is correct, then the metabolic trap hypothesis is wrong.”

Or, “If the metabolic trap hypothesis is correct, then the mechanical paradigm is wrong.”

There seems to be a prevailing notion that both can’t be true. Or, that each may be true for different subsets of people with ME/CFS, but that both surely couldn’t be true for the same population of people with ME/CFS.

I will instead suggest that the mechanical paradigm actually dovetails quite nicely with the metabolic trap hypothesis. I will explain, below.

A Public Conversation

Dr. Phair has been quite generous with his time. He has chosen to directly engage with the online patient community on Phoenix Rising. In one conversation, a patient called Sarah94 asked him why a fusion surgery would eliminate all ME/CFS symptoms, as it did for Jen and for me. In response to Sarah94’s question, Dr. Phair stated the following:

But how did Jen and Jeff get sick in the first place? Surely the absence of steel support is not the cause of the disease. Isn't that cause still unknown?”

In my own case and Jen's case, the ligaments of the craniocervical junction had become too lax to hold in place the skull and upper cervical spine. Ligaments are made of collagen. The craniocervical junction relies on ligaments to provide stability and to prevent excess motion. It is the most mobile portion of the spine. When the skull and upper spine moves too much, as it did in my case and Jen's, it can cause mechanical brainstem compression. This compression caused all of our symptoms of ME. The fusion surgery eliminated all of our ME symptoms because it stabilized our spines, which in turn relieved our brainstem compression.

In short, ligament laxity was the cause of our CCI.

The CCI, in turn, was the cause of our ME/CFS.

Ligament Laxity and the Most Common ME/CFS Triggers

Dr. Phair explained that a common assumption -- that ME/CFS will always have a viral trigger -- is inconsistent with much of what we know about the illness:

“If a viral infection is the cause of ME/CFS then: 1) it’s very difficult to explain all the cases of ME/CFS that do not begin with an infection – the ones beginning with trauma, or surgery, or overtraining, 2) we should be able to find an active infection with the causal virus, not just antibodies to some past infection, or 3) we have to explain why the immune system can successfully clear the viral infection and yet the patient is still sicker than they have ever been in their lives.”

Above, Dr. Phair listed the four most common onset triggers of ME/CFS: Infection, impact trauma, surgery, and overtraining. Another top contender may be mold exposure. It is easy to see how impact trauma, surgery, and overtraining might damage ligaments. But, some people have asked: How could an infection, or mold exposure, lead to ligament damage? A potential answer: Collagen degradation.

We know that ligaments are made of collagen. There is a substantial body of literature suggesting that, in response to an infection, our bodies secrete collagen-degrading enzymes as part of our normal immune response. Infectious triggers can include viral and bacterial pathogens, including tick borne disease. The collagen-degrading enzymes include, but are not limited to, collagenases and and matrix metalloproteinases (MMPs).

But what about mold? There is evidence suggesting that black mold releases proteinases that can degrade collagen. Three mycotoxins have been found to increase the expression of MMPs, resulting in collagen loss.

Genetic Vulnerability, an Environmental Trigger, and Bistability

Dr. Davis and Dr. Phair have shared that their Severely Ill Patient study found a mutation in IDO2 in 100% (20/20) patients. In contrast, only 40% of the general population has this mutation. This is very significant. It suggests that having mutation(s) on the IDO2 gene is a necessary, but not sufficient, condition for becoming severely ill with ME.

From their article, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS:

"Genetics must hold clues to ME/CFS because, like other chronic diseases, there is evidence that this disease can run in families, but it is clearly not a disease one has at birth. Rather, there appears to be a genetic propensity that lies hidden until a particular collection of triggering circumstances arises in the patient’s microbial, dietary, micronutrient, physiological, emotional or physical environment."

Their current hypothesis appears to be that an external trigger causes a genetically-vulnerable person to shift from a healthy steady state to a pathological steady state. Dr. Davis and Dr. Phair refer to this propensity to shift into different steady-states, depending on external conditions or triggers, as bistability. They are hypothesizing that a previously-healthy person, if genetically vulnerable, can experience an environmental trigger that shifts them into a state in which the kynurenine pathway becomes disturbed, directly leading to metabolic and immune dysfunction, to include the symptoms of ME.

The IDO2 Mutation, the Kynurenine Pathway, and the Mechanical Paradigm

With those general principles in mind -- genetic vulnerability, an environmental trigger, and bistability -- I will suggest a fairly specific hypothesis: Perhaps IDO2 mutations make a person genetically vulnerable to collagen problems. Dr. Davis has stated that roughly 50% of people with ME/CFS meet the criteria for Ehlers Danlos Syndrome (EDS), which is defined as a disorder of collagen, characterized in large measure by ligament laxity. : Perhaps IDO2 mutations make a person genetically vulnerable to collagen problems. Dr. Davis has stated that roughly 50% of people with ME/CFS meet the criteria for Ehlers Danlos Syndrome (EDS), which is defined as a disorder of collagen, characterized in large measure by ligament laxity.

Could it be that the observed tryptophan/ kynurenine connection to ME is actually a downstream result of mechanical neurological compression, deformation, or stretching of the brainstem and/or spinal cord? In other words, perhaps these kynurenine/tryptophan findings are the result of a collagen problem. These metabolic findings could potentially have an upstream mechanical basis.

You might ask: “But Jeff, how could a disturbed kynurenine pathway be caused by a mechanical problem, such as faulty collagen -- leading to lax ligaments -- leading to CCI/AAI or cervical stenosis?”

I would say that the nexus could be the autonomic nervous system. Does the autonomic nervous system not play a role in regulating energy metabolism, including the kynurenine pathway? There are reasons to believe that this could be the case.

This article discusses a relationship between the autonomic nervous system, the immune system, and the kynurenine pathway. It examines these relationships in the context of depression, but that doesn’t matter. What matters here is that a relationship between these systems and the kynurenine pathway exists, and it exists within the context of many different illness states.

From the article: “This review focuses on the interaction between stress, the autonomic nervous system (ANS) and the immune system, which can cause imbalances in the kynurenine (KYN) pathway.”

We know that autonomic nervous system functioning is disturbed in people with ME. We also know that autonomic nervous system function can be fully restored by relieving chronic brainstem and spinal cord compression, as in my own case, Jen Brea’s case, and the case of the three women in Peter Rowe’s cervical stenosis case series. All of us exhibited bistability: We shifted from healthy (our lives pre-ME/CFS) to unhealthy (our lives during ME/CFS), back to healthy again (our lives post-fusion). Following our fusions, we shifted from a pathological steady state of ME/CFS into a healthy state. Could this restoration of autonomic function have restored our bodies’ ability to regulate energy metabolism? It's worth considering. Would a patient with ME/CFS, who might have a measurably disturbed kynurenine pathway, see this pathway normalize after their ANS normalizes?

Besides being downstream of ANS dysfunction, are there other ways that the metabolic trap hypothesis might relate to collagen loss, ligament laxity, and CCI/AAI? As one Phoenix Rising member asked: "Does anyone have any insight with regard to how IDO blockade could mediate cranio- cervical stability which myself and others are increasingly often being co-diagnosed with?"

Dr. Phiar answered that different disease processes (atherosclerosis, ME/CFS) could relate to a metabolic trap, and that perhaps CCI could, too.

He wrote: "I decided to give a talk on 'Atherosclerosis and the metabolic trap hypothesis for chronic disease.' To give this talk I just removed the references to ME and added a slide (Tabas Fig 3.) from a recent review on Atherosclerosis detailing the decision that macrophages make to become Resolving or Inflammatory. So atherosclerosis could be just an IDO metabolic trap in another cell type.

The connection to CCI is pretty straightforward from there. With low kynurenine the macrophage differentiation decision goes toward inflammatory macrophages. And Inflammatory macrophages are famous for the vast number of MMPs they secrete into the extracellular space. MMPs are matrix metalloproteinases. These enzymes attack collagen, elastin and (I think) any number of other extracellular structural proteins. You will see immediately how CCI could then be downstream of the IDO metabolic trap."

A Chronic Cause Versus a Transient Trigger

Dr. Phair wrote:

“Metabolic traps are just an alternative hypothesis. Traps are interesting because they do not require a chronic cause. A transient trigger is all you need.”

Dr. Phair’s explanation above is intriguing and consistent with the mechanical paradigm. The same “chronic cause vs transient trigger” principle would hold true for ongoing brainstem/spinal cord compression. A transient trigger, such as any of the most common triggers of ME/CFS (infection, surgery, trauma, overtraining, mold exposure) would be sufficient to damage the ligaments via collagen injury/degradation. This could, in turn, result in a person becoming “trapped” in a state of chronic neurological compromise resulting from ongoing mechanical brainstem and/or spinal cord compression.

Gender, Collagen, and Ligaments

Another piece of the ligament/collagen puzzle, as it relates to ME/CFS? Gender. Evidence suggests that estrogen decreases collagen content, while testosterone increases it. Since ligaments are made of collagen, it is easy to surmise then that women would be more prone to ligament laxity than men, and this could potentially account for the gender ratio observed in ME/CFS. Adult women develop ME at roughly four times the rate as adult men. Interestingly, in children with ME, prior to puberty with the influx of sex hormones, the gender ratio is balanced -- 1:1. This is compelling, in part because these gender differences are consistent with ME/CFS as it relates to mechanical paradigm.

In summary: The common causes of ligament laxity, resulting in CCI/AAI and brainstem/spinal cord compression, would be elegantly consistent with what Dr. Phair wrote about commonly observed ME/CFS triggers. The same triggers that can lead to ME/CFS are the same triggers that can lead to CCI/AAI. Also consistent with both ME/CFS and CCI/AAI is the gender differential observed in these conditions.

Brainstem Compression, the Immune System, and the GI System

As for the connection between brainstem compression and the immune system, I will share my own case, as a general example. I had severe ME from 2014 through 2017. During those years, I had extensive blood work, drawn three times per year, to include both viral and bacteriological titers. With each lab result, my IgM and IgG infectious titers for Epstein Barr, Parvovirus, and Mycoplasma Pneumonia were persistently elevated…

Until I had blood drawn after my halo placement.

The halo mimicked a fusion and relieved my brainstem compression while I awaited my fusion surgery.



Three months into wearing the halo, finally free from years of brainstem compression, I had labs drawn in January, 2018. The results revealed that the viral and bacterial titers had completely normalized -- for the first time in over three years.

One could argue that persistently elevated infectious titers, as mine were (both IgM and IgG), indicate the presence of specific chronic infections. Or, perhaps instead, these elevated titers indicate a more generalized immune dysfunction. I suspect the latter, and, in my own case, it seems this generalized immune dysfunction was directly related to my autonomic nervous system dysfunction.

After my autonomic nervous system (ANS) had normalized, my POTS was gone, as was my PEM. I’m speculating that my immune system was, in turn, able to normalize. There is published literature describing this connection in more detail. See this article regarding the autonomic nervous system’s role in immune regulation.

What about the gastrointestinal dysfunction and microbiome disturbances observed in ME/CFS? There is evidence to suggest that gastrointestinal motility can be under autonomic control. We know that brainstem and/or spinal cord compression leads to autonomic dysfunction, and so, it is logical that gastrointestinal dysfunction would be a downstream result. This could account for the high rates of gastroparesis, small intestinal bacterial overgrowth (SIBO), and other disturbances of the microbiome observed in ME/CFS.

Using my own case as an example, I had chronic SIBO during all of my years of ME. Once my autonomic nervous system normalized after my halo and fusion surgery, my gastrointestinal functioning also normalized. I never had SIBO again.

Escape from Illness: An Exogenous Perturbation

Dr. Davis and Dr. Phair suggest that something needs to happen in order to escape the illness state of ME/CFS. From their recent article, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS:

"Escape from the pathological one (trapped steady-state) requires an exogenous perturbation."

To state this another way, Dr. Davis and Dr. Phair are proposing that an external event needs to happen in order to escape the illness state of ME/CFS. I would suggest that relieving mechanical brainstem and/or spinal cord compression, via a fusion surgery, would qualify as an external event, or an "exogenous perturbation.”

The Mechanical Paradigm: Parsimonious

In my opinion, the Mechanical Paradigm is consistent with many of the important observations shared by Dr. Davis and Dr. Phair. In fact, I don’t see any conflict.

I will also suggest that the Mechanical Paradigm is the simplest unifying explanation for much of what we already know about ME/CFS. It is parsimonious.

The Mechanical Paradigm:
  • Is consistent with the most common ME/CFS triggering events: Infection, mold exposure, surgery, overtraining, and impact trauma.
  • Would account for why ME/CFS tends to cluster in families that have Ehlers Danlos Syndrome (EDS – a disorder defined by faulty connective tissue, to explicitly include ligaments).
  • Is consistent with multiple observations shared by Dr. Davis and Dr. Phair: Genetic vulnerability, an environmental trigger, bistability, and an escape from the pathological steady state via an exogenous perturbation.
  • Would account for the 3:1 female:male gender ratio observed in ME/CFS after puberty, and the 1:1 gender ratio observed before puberty, mediated by the presence/absence of sex hormones.
  • Would account for the derangement of the autonomic nervous system (POTS, etc.) characteristic of ME/CFS.
    • As gastrointestinal motility is under autonomic control, it would account for the high rates of gastroparesis and other GI issues leading to small intestinal bacterial overgrowth (SIBO) and other disturbances of the microbiome observed in ME/CFS.
  • Its premise, taken to the logical surgical conclusion, has been able to result in numerous complete remissions from ME/CFS.
    • Relieving spinal cord compression has resulted in multiple complete ME/CFS remissions (Peter Rowe’s case series).
    • Relieving brainstem compression has resulted in multiple complete ME/CFS remissions (Jen, me, and others).

A Testable Model

The Mechanical Paradigm is eminently testable. We can even test it using validated, readily available tools: MRIs, CTs, etc. I wonder who will take on this project?

We need only look for the presence of brainstem and/or spinal cord compression within a large, representative sample of ME/CFS patients.

In short, the Mechanical Paradigm offers the following:
  • An eminently testable hypothesis.
  • A potential biomarker.
  • An effective treatment.
  • A potential opportunity to alleviate enormous suffering.
 
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pattismith

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@jeff_w you are brilliant, and I believe your theory fits with my own story.

Some ME patients also develops gingivitis and teeth problems with gum resorption, which reflects over activity of MMP triggered by infection.
One of the major bacteria involved in gingivitis was also found in brain of Alzheimer patients, and this bacteria is well known for MMP induction, so it could be another possible trigger for ME/CFS..

https://forums.phoenixrising.me/thr...lzheimer’s-disease-brains.77587/#post-2228600
 

JES

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Obviously i have no respect for the guy, so i don't believe him when he says 100% of patients are either going to die or experience the symptoms he claims. By his metric either Jen or Jeff should not be here, yet they are. And the difference between 0.6% and 50-100% is bogus, no statistical analysis could reconcile them (not to mention the doctors who do the surgery would be tied up in so much litigation by now if all their patients got worse or died that their grandchildren would be dealing with the fallout).
I have respect for the guy and the research he did, but I'd still call the 50% number likely bogus. What's the point of making a surgery if the result is so bad it's a toin coss between life and death? I reckon he is talking about his experience from decades ago, so it might not be useful to rely on this versus actual information from studies. Plus even if that number somehow was accurate, procedures have improved today compared to decades ago.
 

valentinelynx

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Prof. Edwards is speaking from his personal experience, not the systematic evidence. Maybe there is something specific going on in the cases he was referring for surgery that made them unusually dangerous or high risk.

Here is the meta-study of 22 different studies: https://academic.oup.com/neurosurgery/article-abstract/67/5/1396/2563905

I highly doubt that his personal experience is the norm and that these 22 studies represent some extreme bias that suppress the mortality rate from 50% to essentially zero. It’s certainly possible but less likely than the alternative.
I agree. I started a reply to this a couple of days ago and discarded it for being too negative. From what I've read of Dr. Edward's posts on the topic (which isn't much) I got the impression that he's pretty biased against the idea of CCI being a significant factor in ME/CFS or at least against the idea that patients should pursue surgery. He seems to be in the "this is a fad camp". I do not know if his dire assessment of the outcomes of CCI surgery on RA patients is accurate. If it is, then those operations must have been "Hail Mary" passes to try to save already moribund patients. It's also possible that the operations were not done well, especially as we are unaware of any UK surgeons with special expertise in this area.
 

pattismith

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I agree. I started a reply to this a couple of days ago and discarded it for being too negative. From what I've read of Dr. Edward's posts on the topic (which isn't much) I got the impression that he's pretty biased against the idea of CCI being a significant factor in ME/CFS or at least against the idea that patients should pursue surgery. He seems to be in the "this is a fad camp". I do not know if his dire assessment of the outcomes of CCI surgery on RA patients is accurate. If it is, then those operations must have been "Hail Mary" passes to try to save already moribund patients. It's also possible that the operations were not done well, especially as we are unaware of any UK surgeons with special expertise in this area.
This is my point of view. And if I were a rheumatologist who had lost half of his patients from CCI surgery, I would certainly have a biased opinion on the subject!

I started to have a look at the 22 studies in the 2010 review Jen has quoted, and some goes back to the eighties!
I want to look into it to see if some european practices have published anything useful about CCI surgery outcomes before 2010...
 
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Daffodil

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i am humbled by how smart people on this board are. meanwhile i can barely remember the year. :-/

@jeff_w do you think it is just ligament laxity? did you have any arthritic / degenerative changes in the cervical joints as well?

do you think that if there was some reliable way to repair the ligaments (ie stem cells or something similar), that you would not have had to have fusion?

thanks
 

Daffodil

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well lets be realistic. the numbers would still be considered tiny by scientific standards, small enough to still be called anecdotal. I think CCI is still worth pursuing but I can understand outside people thinking it is dangerous...it is neurosurgery afterall
 

pattismith

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. If it is, then those operations must have been "Hail Mary" passes to try to save already moribund patients. It's also possible that the operations were not done well, especially as we are unaware of any UK surgeons with special expertise in this area.
I started to read the 38 studies referenced in this review Jen quoted in her ME page.. The first one is from Dr Grob spine unit:

"Occipitocervical Fusion in Patients With Rheumatoid Arthritis (1999)
Dr Grob (a neurosurgeon in Zurich (switzerland)).
Instability and deformity of the cervical spine caused by rheumatoid arthritis is a well known entity.
Operative intervention is indicated for patients with progressive deformity and when pain is resistant to conservative treatment.
In a series of 39 patients who underwent posterior occipitocervical fusion with a Y plate, 22 patients were observed clinically and radiographically at average 41.5 months after surgery.
In 35 of the 39 patients the main indication for surgery was pain, and in 30 of the 39 patients additional neurologic deficit (radiculopathy or myelopathy) was present.
Thirty-one of the 39 patients had atlantoaxial instability.
The atlantoaxial instability was associated with cranial migration of the dens in 19 patients.
According to the classification of Conaty and Mongan 77.3% patients had satisfactory results and 22.7% had unsatisfactory results.
Of the 30 patients with neurologic deficit, nine patients had a significant improvement.
No patient had a worse result after surgery
.
Solid fusion was seen in all 22 patients at followup.
Seven patients experienced complications directly related to the surgical procedure.
Posterior fixation combined with anterior decompression in the presence of spinal stenosis represents a useful and safe method to treat instability and deformity caused by rheumatoid arthritis.
Early surgical procedures may reduce the complication rate."


After reading this abstract (no dead patient!), it is clear to me that the uk unit where Dr Edwards was working was not the best practice for this kind of patients!
 
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A Testable Model

The Mechanical Paradigm is eminently testable. We can even test it using validated, readily available tools: MRIs, CTs, etc. I wonder who will take on this project?
Reading Jeff's blog has completely changed the way I think about this disease. I am as impatient as anyone to see more research on the mechanical paradigm.

It also reminds me of an old story. There was once a person searching the ground near a lamp post at night. A second person came along and asked:
"What are you looking for?"
"I'm looking for a key"
"Did you accidentally drop a key near this lamp post?"
"I didn't loose it here"
"Then why are you looking here?"
"Because the light is better."
Recent technological developments in Molecular Biology have opened up exciting new vistas. Researchers are eager to make use of this new technology. Most of the recent and ongoing research in ME focuses on Molecular Biology. But the key may not be under that lamp post.
 

Alvin2

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It also reminds me of an old story. There was once a person searching the ground near a lamp post at night. A second person came along and asked:
"What are you looking for?"
"I'm looking for a key"
"Did you accidentally drop a key near this lamp post?"
"I didn't loose it here"
"Then why are you looking here?"
"Because the light is better."
This is called the Streetlight Effect