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.
