Stiffness is the Problem, Hypermobility is a Sign

To think that a connective tissue disorder is solely a hypermobility problem is reductionistic thinking and can be damaging to our patients, worsening prognoses. Surprisingly, the understanding of what is happening at a cellular level is quite limited, even among our EDS specialists. I will attempt to summarize and simplify the concepts of extracellular matrix stiffening in connective tissue disorders as much as I am able in a short blog post!

Stiffness is the problem…hypermobility is a sign

While I very much appreciate the amount of work that has been pushed through our education to realize the complex issues that individuals with hypermobility may have; very rarely is it only hypermobility that is causing issues in this population. In fact, for many that have instability as a prime complaint, inflammation is still the driver that pushes a person from unstable and functional to unstable, non-functional, and painful.

Connective tissue disorders like Ehlers Danlos syndrome, Loeys-Dietz, Marfans, Stickler syndrome, and suspected hypermobility spectrum disorders are all a form of extracellular matrix dysfunction. The extracellular matrix makes up our different types of connective tissue based on the ratio of ingredients within the matrix (collagen, proteoglycans, etc.). So, as one example, if someone has a collagen type 1 mutation, this will affect all collagen type 1 throughout the body. Collagen type 1 is found a good deal in bone, and also tendon, ligaments, skin, and fascia. However, collagen type 1 (along with other components) also has a lot to do with the structural integrity of the interstitial space, which is quite commonly looked over.

The interstitial space of the ECM is the space in between, where much of our cellular function and migration happens, toxins and inflammatory mediators are filtered out of tissue spaces, and cells communicate. The interstitial space, and even the border of the ECM, can be more at risk for structural issues with variations in collagen genes, or other genes that help build the 3-D structure of the matrix or participate in function of this area.

With increasing inflammation responses that can occur in this interstitial space, at some point, it may not be able to keep up with the drainage needed, and a stasis or stiffness will develop. Those with collagen (or other ECM components) variations may have more difficulty managing the inflammation in this space and may be more at risk for developing interstitial stiffness.

This is supported already in a study looking at interstitial stasis that is seen at the fascial structures of those with hEDS at the iliotibial band (Wang, 2023). Can we be seeing this elsewhere? Yes, it seems we are.

ECM stiffness can affect a number of different tissues in different ways…

Depending on where this interstitial inflammation builds up, this will determine what symptoms the individual is having and in what systems. The potential for interstitial stasis varies throughout the body. In COVID, not only has it been found in the neurological tissue, but heavily in the lung interstitium as well, leading to fibrotic changes in the tissue. (Tremblay, 2020, Huang, 2023)

The shift in malleability in the interstitial space can change anatomical structures and also influence the efficiency of function. Inflammation caused by immune system responses and altered homeostasis is associated with structural changes to the ECM leads to ECM stiffening. ECM stiffness can further lead to cellular communication and migration issues, enhancing the chronic self-perpetuating cycle of inflammation and ECM rigidity (Pfisterer, 2021.) We can see this in many different systems of the body for individuals in the population, but the neurological system and the vascular system are two areas of hot topic around our population with connective tissue disorders.

ECM inflammation and stiffness in neurological tissue…

If inflammation irritates the neurological system, breaking through the blood brain barrier, it can affect the functioning of the perineuronal networks. These networks are responsible for neuron conductivity and communication. Those with neurological irritation that affects the perineuronal network can increase (seizure-like activity) or decrease (neural degeneration) neurological communication (Pekny, 2016). Collagen types 2 and 11 help support the 3-D structure of the perineuronal network itself. Those with variations in their Col2 or col11 genetics may be more prone to inflammation causing changes at the perineuronal network. General inflammation that builds up in the interstitial space (collagens type 1, 2, 3, 5, 11) can also eventually change permeability at the blood brain barrier, allowing more irritating things to pass through the barrier and into sensitive neurological tissue like the dura and perineuronal networks. This is the chicken or egg scenario – other types of inflammation and dysfunction can eventually lead to problems elsewhere if not taken care of.

Besides conductivity changes, inflammation can also alter the structure of neurological tissue. If neurological inflammation builds up in the interstitial spaces and is not filtered out appropriately, it can settle in this area (Pekny, 2016, Verkhratsky, 2023). Neuraxial dysfunction from altered spinal cord motion or challenges to spinal stability, as seen in some with hEDS, can create challenges for neurovascular plumbing (Frost, 2024).

Collagen type 1 is the dominant collagen type in dura mater (collagen types 3, 2, 4, and 5 are also found within the layers of the spinal cord tissue). As in other areas of interstitial stiffness, if an individual has an issue with a particular collagen type, they may be more at risk for developing continued structural changes with inflammation that is left untamed. Collagen type 4 is the main structural component of the basement membrane of the blood brain barrier, which is built to keep things from passing into neurological tissue. If chronic inflammation builds up in the interstitial space, or the blood brain barrier is broken down directly, immune cells and pathogens will pass through the barrier system (now more permeable) and into unprotected neurological tissue causing localized and widespread inflammatory changes. With astrocyte and microglia cells trying to respond to this irritation and invasion into the neurological space, they turn from being physiological and helpful to pathological and harmful when cause of inflammation is not removed, and the self-perpetuating cycle of inflammation and tissue ECM breakdown persists.

Adhesions can form around neurological tissue and change the neurological tissue to more fibrous in nature rather than pliable (Verkhratsky, 2023). Chiari malformation is found to have arachnoid adhesions, tonsillar gliosis, tissue thickening, adhesions obstructing the foramen of Magendie, and dural scarring in most individuals (Shao, 2023). Occult tethered cord in the hEDS population demonstrates an increase in mast cells, glial cells, and leukocytes, indicating a neuroimmune response (Klinge, 2022). The adhesions and dural responses in the neurological system can be explained in many with CTDs as the interstitial stasis that has found its way into neurological tissue without a good plumbing system for removal of waste.

Inflammation that is left untended can increase the risk of neurological conditions such as chiari malformation, occult tethered cord syndrome, arachnoiditis, dural adhesions or insufficiencies (tears), seizure like activity, neural degeneration, and hyper reactivity of the neurological system.

ECM inflammation and stiffness in vascular tissue…

Vascular components such as veins and arteries also have basement membranes as barrier systems, and interstitial space that surrounds it. Type 4 collagen is denser in the basement membrane of blood vessels, with some type 15 and 18 also present. Collagen types 1 and 3 are denser in the interstitial space in this vascular area as well. Collagen type 6 provides the space between the interstitial space and the basement membrane. (Manon-Jensen, 2016)

Individuals that have alterations in the collagen type 1 or 3 genes may be more at risk for stasis changes occurring at vasculature with chronic inflammation that has been left uncontrolled. As with the other self-perpetuating cycles, inflammation and collagen breakdown continues and will continue to irritate the blood vessel surroundings.

It has been found that those with vascular compression issues and hypermobility tend to have multiple sites of compression and multiple coexisting conditions, affecting a number of different systems (Sandmann, 2021). This does steer toward a systemic issue being present, affecting the vascular tissue, and also causing systemic wide changes. Alterations in the interstitial matrix of vascular tissue from chronic inflammation that may be more common in CTDs, can be the cause for some. This is usually also combined with anatomical factors that predispose the individual to compressions in certain areas (like lumbar hyperlordosis association with MALS). Changes in vascular interstitial integrity will affect vascular stability and function.

Correcting the problem means reducing inflammation, removing the trigger(s), and restoring ECM mobility if possible…

The issues seem to be spreading like wildfire through systems, diagnosis after diagnosis being given, because it is a system wide interstitial stasis problem (that may be easier to develop with a connective tissue disorder). Depending on the individual it may be general, affecting things like mitochondrial function. It may find its way to the neurological tissue and create the presence of all of the diagnoses found in the neurological phenotype (Petrucci, 2024). It may find its way to the vascular tissue and change the stability throughout the body’s vascular structures, and with added anatomy, seem like someone has multiple “local” sites of vascular compression.

But it all comes down to one thing – the interstitial environment has changed. It has changed in structure and function and the helpful things have not yet been done that would start to break up the self-perpetuating cycle of inflammation driving the charge.

In order to break the cycle, the inflammation needs to be addressed, along with the cause of the inflammation.

To say that someone needs to work on mold, and they will be all better, is yet another reductionistic way to look at all of this. The matrix is inefficient in those with extracellular matrix dysfunctions (connective tissue issues) and most of us are easily exposed these days to many things. Not just mold (or fill-in-the-blank with whatever the specialist told you was the one thing causing it.) Once the bucket overflows, all of the things will need to be addressed. This can include, but is not limited to physical stress and trauma, emotional stress and trauma, environmental toxins (plastics, pesticides, heavy metals, etc.), mold, bacterial infections, viral pathogens, electromagnetic fields, parasites, medication toxicity, etc. Through treating these things, it is important to teach the patient how to do so in the future, in case a re-exposure or flare up occurs.

Equally difficult is figuring out how to work on inflammation. This is luckily because there are so many options now available, but many are financially out-of-pocket for the individual and need to be tried to see if the system favors it. This can include but is not limited to: microcurrent, red light therapy, oxidative therapy, manual therapies like lymphatic drainage or fascial counterstrain, saunas, Epsom salt baths, etc. I think it’s important to note that supplementation for inflammation can be helpful but should be precise. As an example, if we think there is neurological inflammation, we will want something specifically targeting astrocyte and microglia control. Less is more, and precise is better.

Interstitial stasis may be more common in those with 3-D structure changes to the matrix itself, that we can see with connective tissue disorders. The ECM should be malleable and allow for cellular migration and communication to occur. If this space is overwhelmed with inflammation and cannot keep up, the area will become stiff, not malleable, and not conducive to general health maintenance. While local tissue stasis can occur, those with connective tissue issues may be more prone to systemic changes as their connective tissue is different throughout the whole body. Inflammatory drivers from a variety of sources can lead to tissue changes that come in clusters of neurological or vascular pathologies, or both. The inflammation and the drivers of the inflammation need to be treated.

This is not to say everyone can avoid surgery, but it is very difficult to tell what actually needs surgery or what needs inflammation help. Once the inflammation clears it tends to be much clearer on what anatomically still needs additional help. Rather than chasing 10 different anatomical issues that have been offered surgery, maybe it is only one or two after the system homeostasis has been restored.

The bottom line is – before considering surgery for any of these system wide conditions that seem to be spreading – inflammation treatment should be absolutely exhausted with a professional. That way, if surgery is needed, the individual should have the best outcomes and minimize risk of post-surgical complications or recurrence of the issue.

And before you say it, I’ll beat you to it – I don’t know who to see to work on the inflammation with this lens as I haven’t met more than I can count on my hand (and I’m being generous) that understand the role of the ECM throughout the body, and implications of homeostasis trouble with connective tissue disorders based on their genetic composition.

• Frost, N., & Barclay, S. J. (2024). Neuraxial biomechanics, fluid dynamics, and myodural regulation: rethinking management of hypermobility and CNS disorders. Frontiers in Neurology, 15, 1479545.

• Huang, J. J., Wang, C. W., Liu, Y., Zhang, Y. Y., Yang, N. B., Yu, Y. C., ... & Qian, G. Q. (2023). Role of the extracellular matrix in COVID-19. World Journal of Clinical Cases, 11(1), 73.

• Klinge, P. M., Srivastava, V., McElroy, A., Leary, O. P., Ahmed, Z., Donahue, J. E., ... & Gokaslan, Z. L. (2022). Diseased filum terminale as a cause of tethered cord syndrome in Ehlers-Danlos syndrome: histopathology, biomechanics, clinical presentation, and outcome of filum excision. World Neurosurgery.

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• Petrucci, T., Barclay, S. J., Gensemer, C., Morningstar, J., Daylor, V., Byerly, K., ... & Norris, R. A. (2024). Phenotypic clusters and multimorbidity in hypermobile Ehlers-Danlos syndrome. Mayo Clinic Proceedings: Innovations, Quality & Outcomes, 8(3), 253-262.

• Pfisterer, K., Shaw, L. E., Symmank, D., & Weninger, W. (2021). The extracellular matrix in skin inflammation and infection. Frontiers in cell and developmental biology, 9, 682414.

• Sandmann, W., Scholbach, T., & Verginis, K. (2021, December). Surgical treatment of abdominal compression syndromes: The significance of hypermobility‐related disorders. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics (Vol. 187, No. 4, pp. 570-578). Hoboken, USA: John Wiley & Sons, Inc..

• Shao, B., Wojcik, D., Ma, K. L., Amaral-Nieves, N., Poggi, J. A., Leary, O. P., & Klinge, P. M. (2023). Reappraisal of intradural findings in Chiari malformation type I. Neurosurgical Focus, 54(3), E2. diseases. Acta neuropathologica, 131, 323-345

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• Wang TJ, Stecco A, Schleip R, Stecco C, Pirri C. Change in gliding properties of the iliotibial tract in hypermobile Ehlers-Danlos Syndrome. J Ultrasound. 2023 Dec;26(4):809-813. doi: 10.1007/s40477-023-00775-7. Epub 2023 Feb 19. PMID: 36802027; PMCID: PMC10632250.