The Mechanical Basis of ME/CFS and, possibly, Long Covid
In 2017, I solved my own case of ME/CFS after tinkering with research for several years. Then, in 2018, I developed a novel model of the disease: The Mechanical Model.
The idea is that ME/CFS may be caused by a physical injury to our neural tissues. The injury can be triggered by a virus, an impact trauma, or other events. Structural neurological conditions involving our connective tissue, such as craniocervical instability (CCI), could be one type of injury that can cause ME/CFS.
Mechanical conditions may be the cause of ME for a significant percentage of people – or possibly for the majority, or even all. These mechanical concepts, involving neural injury in a setting of compromised connective tissue, may also be relevant to Long COVID.
My strongest focus has been on craniocervical instability (CCI) as a potential cause of ME/CFS. Other relevant mechanical conditions, that could cause or contribute to ME/CFS symptoms, include intracranial hypertension, tethered cord syndrome, Chiari malformations, Eagle’s syndrome, and cervical stenosis.
Since proposing the Mechanical Paradigm, the number one question people have asked me is: “Jeff, are you saying everyone with ME has CCI, and that everyone with ME will need neurosurgery?”
In short — not necessarily! First, we do not yet know what percentage of people with ME have CCI or other underlying structural conditions. My hypothesis is that mechanical neurological conditions may be the underlying cause for many, or perhaps all, but we need further research to confirm or disprove this. Secondly, out of those with ME that have had these conditions confirmed, some have been able to address the problem non-surgically, such as with regenerative medicine.
(Image by kalhh from Pixabay)
Read more about the Mechanical Model in a piece I wrote for Health Rising:
Could ME/CFS be a Chronic, Ongoing Brain and Spinal Cord Injury — Exacerbated by Exertion?
The second most frequent question people ask me is: “Jeff, how does the Mechanical Paradigm relate to the Metabolic Trap Hypothesis proposed by Dr. Davis and Dr. Phair?"
In short: It doesn’t.
The Mechanical Paradigm and the Metabolic Trap Hypothesis are very different ways of thinking about ME/CFS. They are distinct concepts. At the same time, they are not inconsistent or conflicting.
Let's dive in, 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 asked him why a fusion surgery would eliminate ME/CFS symptoms, as it did for me and now multiple others. In response to that question, Dr. Phair replied:
“Surely the absence of steel support is not the cause of the disease. Isn't that cause still unknown?”
To address Dr. Phair's question: In my own case, and in the case of some others with ME, the joints and ligaments of the craniocervical junction had become unable to hold in place the skull and upper cervical spine. The craniocervical junction relies in part on the connective tissue of ligaments and joints. Without competent connective tissue, these joints can become unstable, failing to limit excess motion. This is the most mobile portion of the spine. When the skull and upper spine move too much, as in cases of craniocervical instability (CCI), this can cause mechanical deformative stress on the brainstem.
Stabilizing the craniocervical junction can eliminate symptoms by preventing excess mobility. Whether this is accomplished by a fusion or by regenerative medicine, the goal is to relieve the mechanical stress on the brainstem.
But why would our joints fail, and our ligaments become lax, in the first place? There are multiple possibilities.
Collagen, Ligament Laxity, and the Most Common ME/CFS Triggers
Some people believe that ME/CFS will always have a viral trigger. While many cases of ME/CFS do begin with a virus, there are other types of onsets as well. In fact, the four most common onset triggers of ME/CFS are infection, impact trauma, surgery, and overtraining — as found by Dr. Davis and Dr. Phair. From what I and others have observed, another potential contender may be mold exposure.
Dr. Phair expands on this:
“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.”
It is easy to see how impact trauma, surgery, and overtraining might damage ligaments or otherwise strain the connective tissue. After all, those are all physical events. But how might an infection, or mold exposure, lead to connective tissue damage?
We know that ligaments are made of collagen. There is a body of scientific literature suggesting that, in response to an infection, our bodies secrete collagen-degrading enzymes as part of our normal immune response. Whether an infection is tick born, viral, bacterial, doesn’t seem to matter. Any of those infections could initiate a breakdown of collagen. The collagen-degrading enzymes include collagenases and and matrix metalloproteinases (MMPs).
But what about mold? There is evidence suggesting that black mold can degrade collagen through the release of proteinases. In fact, three mycotoxins have been found to increase the expression of MMPs, resulting in collagen loss.
It may be that some people with ME/CFS have an underlying connective tissue disorder, making their collagen more vulnerable to degradation and other types of damage. In fact, I believe this is likely, for multiple reasons that I'll explain a bit later.
Biological Sex, Collagen, and Ligaments
Another piece of the connective tissue puzzle, as it could relate to ME/CFS? Biological sex.
First, let’s acknowledge that the concepts of gender and biology are interesting and complex. Here, I’m discussing mundane averages that don’t reflect the full spectrum of possible combinations.
Evidence suggests that estrogen decreases collagen content, while testosterone increases it. Since ligaments are made of collagen, perhaps women would be more prone to ligament laxity than men, consistent with the sex ratio observed in ME/CFS. Adult women develop ME at roughly three to 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 interesting, in part, because these gender differences are consistent with ME/CFS.
In summary: The common causes of ligament laxity or other connective tissue degradation could be consistent with each of the most commonly observed ME/CFS triggers: infection, impact trauma, surgery, and overtraining. Also, the same vulnerabilities and triggers that can lead to ME/CFS, including genetic connective tissue disorders, are known to be associated with CCI/AAI, Chiari, tethered cord, and other mechanical conditions. The gender differential, too, is consistent with both ME/CFS and underlying mechanical conditions involving ligament laxity.
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 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 state shifting, in response to external conditions or triggers, as bistability.
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 connective tissue problems, such as 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.
One question I have is this: 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 connective tissue leading to lax ligaments or an abnormal filum?
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 it could.
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, illustrating that a relationship between these systems and the kynurenine pathway exists. It also 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, and in 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.
Also: Would a patient with ME/CFS, who might have a measurably disturbed kynurenine pathway while sick, have 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: "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."
Mechanical Brainstem Deformation, the Immune System, and the GI System
As for the connection between mechanical brainstem deformation and the immune system, I will share my own case, as a general example. During my years with severe ME, 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. It stabilized my craniocervical junction, relieving the CCI. I was free from brainstem deformation while I awaited my fusion surgery.
Three months into wearing the halo, I had labs drawn in January, 2018. The results revealed that the viral and bacterial titers had 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.
The vagus nerve is the longest nerve of the autonomic nervous system. Researcher Michael VanElzakker has hypothesized that ME could result from a vagus nerve infection. What I find especially elegant about this hypothesis is that vagus nerve involvement could account for many observed aspects of ME/CFS. I would suggest a different interpretation of the vagus nerve’s involvement: Perhaps mechanical deformation of the vagus nerve, as is seen with craniocervical instability (CCI), could contribute to the chronic immune dysfunction and gastrointestinal dysfunction often seen 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 could 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 an outside event needs to happen in order to escape the illness state of ME/CFS. From their article, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS:
"Escape from the pathological one (trapped steady-state of ME/CFS) requires an exogenous perturbation."
Their idea that an external event needs to happen in to escape ME/CFS is consistent with the Mechanical Paradigm. Relieving mechanical brainstem and/or spinal cord deformation, via a fusion surgery, regenerative medicine, tethered cord surgery, or another method, would surely qualify as an external event, or an "exogenous perturbation.”
In fact, those specific events have, in multiple cases, provided an escape from this illness.
The Mechanical Paradigm: Parsimonious
I will suggest that the Mechanical Paradigm is the most complete unifying explanation for much of what we already know about ME/CFS. It also follows the principle of making as few assumptions as necessary to account for what is being observed. This is often referred to as Occam’s razor, also known as the principle of parsimony.
The Mechanical Paradigm:
Is consistent with the most common ME/CFS triggering events: Infection, surgery, overtraining, impact trauma, and mold exposure.
Could potentially 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).
Could potentially 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.
Could potentially account for the derangement of the autonomic nervous system (POTS, etc.) characteristic of ME/CFS.
Could potentially account for the high rates of gastroparesis, other GI issues, small intestinal bacterial overgrowth (SIBO), and additional disturbances of the microbiome observed in ME/CFS. Gastrointestinal motility can be under autonomic control.
Its premise, taken to its logical treatment conclusions, has resulted in many improvements or complete remissions from ME/CFS.
Relieving spinal cord compression has resulted in multiple complete ME/CFS remissions (Peter Rowe’s case series).
Relieving brainstem deformation from CCI, and spinal cord stretching from tethered cord, has resulted in multiple people having complete ME/CFS remissions.
A Testable Model
A new model of a disease needs to be testable.
The Mechanical Paradigm is very testable. We need only look for the presence of mechanical neurological conditions within a large, representative sample of ME/CFS patients.
We can even do this using validated, readily available tools: MRIs, CTs, intracranial bolt testing, etc.
In short, the Mechanical Paradigm offers the following:
An eminently testable hypothesis.
Multiple potential biomarkers.
Multiple potential treatments.
A potential opportunity to alleviate enormous suffering.